RÉSUMÉ
The primary emphasis of photoimmunology is the impact of nonionizing radiation on the immune system. With the development of terahertz (THz) and sub-terahertz (sub-THz) technology, the biological effects of this emerging nonionizing radiation, particularly its influence on immune function, remain insufficiently explored but are progressively attracting attention. Here, we demonstrated that 0.1 sub-THz radiation can modulate the immune system and alleviate symptoms of arthritis in collagen-induced arthritis (CIA) mice through a nonthermal manner. The application of 0.1 sub-THz irradiation led to a decrease in proinflammatory factors within the joints and serum, reducing the levels of blood immune cells and the quantity of splenic CD4+ T cells. Notably, 0.1 sub-THz irradiation restored depleted Treg cells in CIA mice and re-established the Th17/Treg equilibrium. These findings suggested that sub-THz irradiation plays a crucial role in systemic immunoregulation. Further exploration of its immune modulation mechanisms revealed the anti-inflammatory properties of 0.1 sub-THz on LPS-stimulated skin keratinocytes. Through the reduction in NF-κB signaling and NLRP3 inflammasome activation, 0.1 sub-THz irradiation effectively decreased the production of inflammatory factors and immune-active substances, including IL-1ß and PGE2, in HaCaT cells. Consequently, 0.1 sub-THz irradiation mitigated the inflammatory response and contributed to the maintenance of immune tolerance in CIA mice. This research provided significant new evidence supporting the systemic impacts of 0.1 sub-THz radiation, particularly on the immune system. It also enhanced the field of photoimmunology and offered valuable insights into the potential biomedical applications of 0.1 sub-THz radiation for treating autoimmune diseases.
Sujet(s)
Arthrite expérimentale , Animaux , Arthrite expérimentale/immunologie , Arthrite expérimentale/radiothérapie , Arthrite expérimentale/anatomopathologie , Souris , Rayonnement térahertz , Anti-inflammatoires/pharmacologie , Anti-inflammatoires/usage thérapeutique , Mâle , Protéine-3 de la famille des NLR contenant un domaine pyrine/métabolisme , Inflammasomes/métabolisme , Inflammasomes/immunologie , Facteur de transcription NF-kappa B/métabolisme , Souris de lignée DBA , Lymphocytes T régulateurs/immunologie , Lymphocytes T régulateurs/effets des radiations , Humains , Transduction du signal/effets des radiations , Kératinocytes/effets des radiations , Kératinocytes/immunologie , Kératinocytes/métabolismeRÉSUMÉ
BACKGROUND: As the largest organ of the body, the skin is constantly subjected to ultraviolet radiation (UVR), leading to inflammations and changes that mirror those seen in chronological aging. Although various small molecule drugs have been explored for treating skin photoaging, they typically suffer from low stability and a high incidence of adverse reactions. Consequently, the continued investigation of photoaging treatments, particularly those utilizing herbal products, remains a critical clinical endeavor. One such herbal product, Lapagyl, is derived from the bark of the lapacho tree and possesses antioxidant efficacies that could be beneficial in combating skin photoaging. PURPOSE: This research aimed to evaluate the efficacy of the herbal product Lapagyl in combating UVR-induced skin photoaging. Additionally, it sought to unravel the mechanisms by which Lapagyl promotes the regeneration of the skin extracellular matrix. METHODS: To investigate whether Lapagyl can alleviate skin aging and damage, a UVR radiation model was established using SKH-1 hairless mice. The dorsal skins of these mice were evaluated for wrinkle formation, texture, moisture, transepidermal water loss (TEWL), and elasticity. Pathological assessments were conducted to determine Lapagyl's efficacy. Additionally, single-cell sequencing and spectrum analysis were employed to elucidate the working mechanisms and primary components of Lapagyl in addressing UVR-induced skin aging and injury. RESULTS: Lapagyl markedly reduced UVR-induced wrinkles, moisture loss, and elasticity decrease in SKH-1 mice. Single-cell sequencing demonstrated that Lapagyl corrected the imbalance in cell proportions caused by UVR, decreased UVR-induced ROS expression, and protected basal and spinous cells from skin damage. Additionally, Lapagyl effectively prevented the entry of inflammatory cells into the skin by reducing CCL8 expression and curtailed the UVR-induced formation of Foxp3+ regulatory T cells (Tregs) in the skin. Both pathological assessments and ex vivo skin model results demonstrated that Lapagyl effectively reduced UVR-induced damage to collagen and elastin. Spectrum analysis identified Salidroside as the primary compound remaining in the skin following Lapagyl treatment. Taken together, our study elucidated the skin protection mechanism of the herbal product Lapagyl against UVR damage at the cellular level, revealing its immunomodulatory effects, with salidroside identified as the primary active compound for skin. CONCLUSION: Our study provided a thorough evaluation of Lapagyl's protective effects on skin against UVR damage, delving into the mechanisms at the cellular level. We discovered that Lapagyl mitigates skin inflammation and immunosuppression by regulating Foxp3+ Tregs and the CCL pathway. These insights indicate that Lapagyl has potential as a novel therapeutic option for addressing skin photoaging.
Sujet(s)
Facteurs de transcription Forkhead , Souris hairless , Vieillissement de la peau , Peau , Lymphocytes T régulateurs , Rayons ultraviolets , Animaux , Femelle , Souris , Antioxydants/pharmacologie , Chimiokines/métabolisme , Facteurs de transcription Forkhead/métabolisme , Inflammation , Peau/effets des médicaments et des substances chimiques , Peau/effets des radiations , Vieillissement de la peau/effets des médicaments et des substances chimiques , Vieillissement de la peau/effets des radiations , Lymphocytes T régulateurs/effets des médicaments et des substances chimiques , Lymphocytes T régulateurs/effets des radiations , Transcriptome/effets des médicaments et des substances chimiquesRÉSUMÉ
PURPOSE: The complex strategy of hypo-fractionated radiotherapy (HFRT) in combination with an immune checkpoint inhibitor (ICI) can stimulate a potential systemic antitumor response; however, the abscopal effect is always precluded by the tumor microenvironment, which may limit sufficient T-cell infiltration of distant nonirradiated tumors for certain kinds of inhibitory factors, such as regulatory T-cells (Tregs). Additionally, low-dose cyclophosphamide (LD-CYC) can specifically kill regulatory Tregs and strongly synergize antigen-specific immune responses, which could promote an abscopal effect. MATERIALS AND METHODS: We explored whether a triple regimen consisting of HFRT, ICI, and LD-CYC could achieve a better systemic antitumor response in bilateral mouse tumor models. RESULT: Our data demonstrate that LD-CYC combined with HFRT and antiprogrammed cell death ligand 1 (PDL-1) therapy could enhance the abscopal effect than only HFRT/antiPDL-1 or HFRT alone. Surprisingly, repeat CYC doses cannot further restrain tumor proliferation but can prolong murine overall survival, as revealed by the major pathologic responses. These results are associated with increased CD8 + effector T-cell infiltration, although LD-CYC did not upregulate PDL-1 expression in the tumor. CONCLUSIONS: Compared with traditional strategies, for the first time, we demonstrated that a triple treatment strategy remarkably increased the number of radiation-induced tumor-infiltrating CD8 + T-cells, effectively decreasing infiltrating Tregs, and promoting an abscopal effect. Thus, we describe a novel and effective therapeutic approach by combining multiple strategies to target several tumor-mediated immune inhibitory mechanisms.
Sujet(s)
Cyclophosphamide , Inhibiteurs de points de contrôle immunitaires , Lymphocytes T régulateurs , Microenvironnement tumoral , Animaux , Cyclophosphamide/pharmacologie , Cyclophosphamide/administration et posologie , Cyclophosphamide/usage thérapeutique , Souris , Inhibiteurs de points de contrôle immunitaires/pharmacologie , Inhibiteurs de points de contrôle immunitaires/usage thérapeutique , Microenvironnement tumoral/effets des médicaments et des substances chimiques , Microenvironnement tumoral/effets des radiations , Microenvironnement tumoral/immunologie , Lymphocytes T régulateurs/immunologie , Lymphocytes T régulateurs/effets des médicaments et des substances chimiques , Lymphocytes T régulateurs/effets des radiations , Femelle , Association thérapeutique , Modèles animaux de maladie humaine , Mélanome expérimental/anatomopathologie , Mélanome expérimental/immunologie , Mélanome expérimental/traitement médicamenteux , Mélanome expérimental/radiothérapie , Rayonnement ionisant , Antigène CD274/antagonistes et inhibiteurs , Antigène CD274/métabolisme , Antinéoplasiques alcoylants/pharmacologie , Antinéoplasiques alcoylants/usage thérapeutique , Antinéoplasiques alcoylants/administration et posologie , Souris de lignée C57BL , Humains , Lignée cellulaire tumoraleRÉSUMÉ
Outcomes for triple negative breast cancer (TNBC) are poor and may be improved by increasing CD8+ tumor infiltrating lymphocytes (TIL) to augment antitumor immunity. Radiation (RT) can promote immunogenic cell death with increased antitumor T cell activity but also stimulates suppressive regulatory T cells (Tregs). Because metabolic alterations affect immune homeostasis and prior studies show caloric restriction (CR) combined with RT improves preclinical TNBC outcomes, we hypothesized that CR augments RT, in part, by altering intratumoral immunity. Using an in vivo model of TNBC, we treated mice with ad libitum (AL) diet, radiation, a CR diet, or CR + RT, and demonstrated an immune suppressive environment with a significant increase in CD4+ CD25+Foxp3+ Tregs after RT but not in CR-fed mice. CD8:Treg ratio in CR + RT TIL increased 4-fold compared with AL + RT mice. In vivo CD8 depletion was performed to assess the role of effector T cells in mitigating the effects of CR, and it was found that in mice undergoing CR, depletion of CD8 T cells resulted in increased tumor progression and decreased median survival compared with isotype control-treated mice. In addition, PD-1 expression on CD3+CD8+ T cells within the tumor microenvironment was significantly increased in CR + RT versus AL + RT treated mice as per immunofluorescence. Serum from breast cancer patients undergoing RT alone or CR and RT was collected pre- and postintervention, and a cytokine array demonstrated that patients treated with CR + RT had notable decreases in immunosuppressive cytokines such as IL-2Rγ, IL-10Rß, and TGF-ß2 and 3 compared with patients receiving RT alone. In conclusion, combining CR with RT decreases intratumoral Tregs, increases CD8:Treg, and increases PD-1 expression via a process dependent on CD8 T cells in a TNBC model. Breast cancer patients undergoing CR concurrently with RT also had significant reduction in immunosuppressive cytokine levels compared with those receiving RT alone.
Sujet(s)
Restriction calorique , Lymphocytes TIL/effets des radiations , Lymphocytes T régulateurs/effets des radiations , Tumeurs du sein triple-négatives/radiothérapie , Microenvironnement tumoral/effets des radiations , Adulte , Sujet âgé , Animaux , Lymphocytes T CD4+/composition chimique , Lymphocytes T CD4+/cytologie , Lymphocytes T CD4+/immunologie , Lymphocytes T CD4+/effets des radiations , Lymphocytes T CD8+/composition chimique , Lymphocytes T CD8+/métabolisme , Lymphocytes T CD8+/effets des radiations , Association thérapeutique/méthodes , Évolution de la maladie , Femelle , Cytométrie en flux , Facteurs de transcription Forkhead , Humains , Sous-unité gamma commune aux récepteurs des interleukines/sang , Sous-unité bêta du récepteur à l'interleukine-10/sang , Sous-unité alpha du récepteur à l'interleukine-2 , Déplétion lymphocytaire/méthodes , Lymphocytes TIL/cytologie , Lymphocytes TIL/immunologie , Souris , Souris de lignée BALB C , Adulte d'âge moyen , Récepteur-1 de mort cellulaire programmée/métabolisme , Répartition aléatoire , Lymphocytes T régulateurs/cytologie , Lymphocytes T régulateurs/immunologie , Facteur de croissance transformant bêta-2/sang , Facteur de croissance transformant bêta-3/sang , Tumeurs du sein triple-négatives/sang , Tumeurs du sein triple-négatives/immunologie , Tumeurs du sein triple-négatives/mortalité , Microenvironnement tumoral/immunologieRÉSUMÉ
PURPOSE: Radiation therapy (RT) modulates the immune characteristics of the tumor microenvironment (TME). It is not known whether these effects are dependent on the type of RT used. METHODS AND MATERIALS: We evaluated the immunomodulatory effects of carbon-ion therapy (CiRT) compared with biologically equivalent doses of photon therapy (PhRT) on solid tumors. Orthotopic 4T1 mammary tumors in immunocompetent hosts were treated with CiRT or biologically equivalent doses of PhRT. Seventy-two hours after RT, tumors were harvested and the immune characteristics of the TME were quantified by flow cytometry and multiplex cytokine analyses. RESULTS: PhRT decreased the abundance of CD4+ and CD8+ T cells in the TME at all doses tested, with compensatory increases in proliferation. By contrast, CiRT did not significantly alter CD8+ T-cell infiltration. High-dose CiRT increased secretion of proinflammatory cytokines by tumor-infiltrating CD8+ T cells, including granzyme B, IL-2, and TNF-α, with no change in IFN-γ. Conversely, high-dose PhRT increased CD8+ T-cell secretion of IFN-γ only. At most of the doses studied, PhRT increased proliferation of immunosuppressive regulatory T cells; this was only seen with high-dose CiRT. Cytokine analyses of bulk dissociated tumors showed that CiRT significantly increased levels of IFN-γ, IL-2, and IL-1ß, whereas PhRT increased IL-6 levels alone. CONCLUSIONS: At low doses, lymphocytes differ in their sensitivity to CiRT compared with PhRT. Unlike PhRT, low-dose CiRT is generally lymphocyte-sparing. At higher doses, CiRT is a more potent inducer of proinflammatory cytokines and merits further study as a modulator of the immunologic characteristics of the TME.
Sujet(s)
Lymphocytes T CD4+/effets des radiations , Lymphocytes T CD8+/effets des radiations , Radiothérapie par ions lourds , Tumeurs mammaires de l'animal/radiothérapie , Photons/usage thérapeutique , Microenvironnement tumoral/effets des radiations , Animaux , Lymphocytes T CD4+/métabolisme , Lymphocytes T CD8+/métabolisme , Femelle , Cytométrie en flux , Granzymes/métabolisme , Granzymes/effets des radiations , Immunocompétence , Interféron gamma/métabolisme , Interféron gamma/effets des radiations , Interleukine-1 bêta/métabolisme , Interleukine-1 bêta/effets des radiations , Interleukine-2/métabolisme , Interleukine-2/effets des radiations , Interleukine-6/métabolisme , Interleukine-6/effets des radiations , Tumeurs mammaires de l'animal/immunologie , Souris , Efficacité biologique relative , Lymphocytes T régulateurs/cytologie , Lymphocytes T régulateurs/effets des radiations , Microenvironnement tumoral/immunologie , Facteur de nécrose tumorale alpha/métabolisme , Facteur de nécrose tumorale alpha/effets des radiationsRÉSUMÉ
Radiation enteritis is one of the most common side effects of ionizing radiation in patients with pelvic cancers. Increasing amounts of evidence indicate that pro-inflammatory responses significantly contribute to the development of radiation enteritis. In this study, we investigated the association between T regulatory (Treg) cells and the risk of developing radiation enteritis in cervical cancer patients. The following observations were made. First, the frequencies of CD25hiFoxp3+ Treg cells were significantly lower in patients with radiation enteritis than in both healthy subjects and cervical cancer patients without radiation enteritis. Also, patients with the more severe grade 3 enteritis presented significantly lower Treg levels than patients with the more common grade 1 enteritis. Second, the expression of several molecules associated with Treg function, including CTLA-4, IL-10, TGF-ß, and perforin, was significantly lower in patients with radiation enteritis than in healthy subjects. In patients without radiation enteritis, however, only CTLA-4, but not other Treg-associated suppressive molecules, was reduced in Treg cells. Third, Treg cells can markedly suppress CD8 T cell proliferation, but in patients with radiation enteritis, this function of Treg cells was significantly impaired, in a manner that was associated with lower CTLA-4 expression. Overall, these data suggest that the frequency and function of Treg cells is negatively associated with the risk of developing enteritis following radiation. In clinical practice, the characteristics of Treg cells may be considered to evaluate the risk of developing enteritis if the cancer patient is receiving ionizing radiation.
Sujet(s)
Antigène CTLA-4/métabolisme , Entérite/immunologie , Lésions radiques/immunologie , Lymphocytes T régulateurs/effets des radiations , Tumeurs du col de l'utérus/radiothérapie , Études cas-témoins , Entérite/sang , Entérite/diagnostic , Femelle , Études de suivi , Volontaires sains , Humains , Activation des lymphocytes/effets des radiations , Lésions radiques/sang , Lésions radiques/diagnostic , Indice de gravité de la maladie , Lymphocytes T régulateurs/immunologie , Lymphocytes T régulateurs/métabolismeRÉSUMÉ
Immune checkpoint inhibitors targeting programmed cell death 1 (PD-1), programmed cell death ligand-1 (PD-L1), and others have shown potent clinical efficacy and have revolutionized the treatment protocols of a broad spectrum of tumor types, especially non-small-cell lung cancer (NSCLC). Despite the substantial optimism of treatment with PD-1/PD-L1 inhibitors, there is still a large proportion of patients with advanced NSCLC who are resistant to the inhibitors. Preclinical and clinical trials have demonstrated that radiotherapy can induce a systemic antitumor immune response and have a great potential to sensitize refractory "cold" tumors to immunotherapy. Stereotactic body radiation therapy (SBRT), as a novel radiotherapy modality that delivers higher doses to smaller target lesions, has shown favorable antitumor effects with significantly improved local and distant control as well as better survival benefits in various solid tumors. Notably, research has revealed that SBRT is superior to conventional radiotherapy, possibly because of its more powerful immune activation effects. Thus, PD-1/PD-L1 inhibitors combined with SBRT instead of conventional radiotherapy might be more promising to fight against NSCLC, further achieving more favorable survival outcomes. In this review, we focus on the underlying mechanisms and recent advances of SBRT combined with PD-1/PD-L1 inhibitors with an emphasis on some future challenges and directions that warrant further investigation.
Sujet(s)
Antinéoplasiques/usage thérapeutique , Carcinome pulmonaire non à petites cellules/radiothérapie , Inhibiteurs de points de contrôle immunitaires/usage thérapeutique , Immunité/effets des radiations , Tumeurs du poumon/radiothérapie , Radiochirurgie , Antigènes néoplasiques/immunologie , Antinéoplasiques/effets indésirables , Antinéoplasiques immunologiques/effets indésirables , Antinéoplasiques immunologiques/usage thérapeutique , Antigène CD274/antagonistes et inhibiteurs , Antigène CD274/physiologie , Marqueurs biologiques , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Carcinome pulmonaire non à petites cellules/immunologie , Chimiotaxie des leucocytes/effets des radiations , Essais cliniques comme sujet , Association thérapeutique , Résistance aux médicaments antinéoplasiques , Humains , Inhibiteurs de points de contrôle immunitaires/effets indésirables , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/immunologie , Lymphocytes TIL/immunologie , Lymphocytes TIL/effets des radiations , Études multicentriques comme sujet , Protéines tumorales/antagonistes et inhibiteurs , Récepteur-1 de mort cellulaire programmée/antagonistes et inhibiteurs , Récepteur-1 de mort cellulaire programmée/physiologie , Survie sans progression , Hypofractionnement de dose , Radiochirurgie/effets indésirables , Radiochirurgie/méthodes , Planification de radiothérapie assistée par ordinateur , Lymphocytes T régulateurs/immunologie , Lymphocytes T régulateurs/effets des radiations , Résultat thérapeutique , Échappement de la tumeur à la surveillance immunitaireRÉSUMÉ
Radiotherapy can induce the infiltration of immune suppressive cells which are involved in promoting tumor progression and recurrence. A number of natural products with immunomodulating abilities have been gaining attention as complementary cancer treatments. This attention is partly due to therapeutic strategies which have proven to be ineffective as a result of tumorinduced immunosuppressive cells found in the tumor microenvironment. The present study investigated whether HS1793, a resveratrol analogue, can enhance the antitumor effects by inhibiting lymphocyte damage and immune suppression by regulatory T cells (Tregs) and tumorassociated macrophages (TAMs), during radiation therapy. FM3A cells were used to determine the role of HS1793 in the radiationinduced tumor immunity of murine breast cancer. HS1793 treatment with radiation significantly increased lymphocyte proliferation with concanavalin A (Con A) stimulation and reduced the DNA damage of lymphocytes in irradiated tumorbearing mice. The administration of HS1793 also decreased the number of Tregs, and reduced interleukin (IL)10 and transforming growth factor (TGF)ß secretion in irradiated tumorbearing mice. In addition, HS1793 treatment inhibited CD206+ TAM infiltration in tumor tissue when compared to the controls or irradiation alone. Mechanistically, HS1793 suppressed tumor growth via the activation of effector T cells in irradiated mice. On the whole, the findings of the present study reveal that HS1793 treatment improves the outcome of radiation therapy by enhancing antitumor immunity. Indeed, HS1793 appears to be a good therapeutic candidate for use in combination with radiotherapy in breast cancer.
Sujet(s)
Interleukine-10/métabolisme , Tumeurs expérimentales de la mamelle/thérapie , Naphtols/administration et posologie , Radiosensibilisants/administration et posologie , Résorcinol/administration et posologie , Facteur de croissance transformant bêta/métabolisme , Animaux , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Survie cellulaire/effets des médicaments et des substances chimiques , Chimioradiothérapie , Concanavaline A/pharmacologie , Femelle , Tumeurs expérimentales de la mamelle/immunologie , Souris , Naphtols/pharmacologie , Radiosensibilisants/pharmacologie , Résorcinol/pharmacologie , Lymphocytes T régulateurs/effets des médicaments et des substances chimiques , Lymphocytes T régulateurs/effets des radiations , Résultat thérapeutique , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
BACKGROUND: The use of immunotherapy strategies for the treatment of advanced cancer is rapidly increasing. Most immunotherapies rely on induction of CD8+ tumor-specific cytotoxic T cells that are capable of directly killing cancer cells. Tumors, however, utilize a variety of mechanisms that can suppress anti-tumor immunity. CD4+ regulatory T cells can directly inhibit cytotoxic T cell activity and these cells can be recruited, or induced, by cancer cells allowing escape from immune attack. The use of ionizing radiation as a treatment for cancer has been shown to enhance anti-tumor immunity by several mechanisms including immunogenic tumor cell death and phenotypic modulation of tumor cells. Less is known about the impact of radiation directly on suppressive regulatory T cells. In this study we investigate the direct effect of radiation on human TREG viability, phenotype, and suppressive activity. RESULTS: Both natural and TGF-ß1-induced CD4+ TREG cells exhibited increased resistance to radiation (10 Gy) as compared to CD4+ conventional T cells. Treatment, however, decreased Foxp3 expression in natural and induced TREG cells and the reduction was more robust in induced TREGS. Radiation also modulated the expression of signature iTREG molecules, inducing increased expression of LAG-3 and decreased expression of CD25 and CTLA-4. Despite the disconcordant modulation of suppressive molecules, irradiated iTREGS exhibited a reduced capacity to suppress the proliferation of CD8+ T cells. CONCLUSIONS: Our findings demonstrate that while human TREG cells are more resistant to radiation-induced death, treatment causes downregulation of Foxp3 expression, as well as modulation in the expression of TREG signature molecules associated with suppressive activity. Functionally, irradiated TGF-ß1-induced TREGS were less effective at inhibiting CD8+ T cell proliferation. These data suggest that doses of radiotherapy in the hypofractionated range could be utilized to effectively target and reduce TREG activity, particularly when used in combination with cancer immunotherapies.
Sujet(s)
Lymphocytes T CD4+/immunologie , Lymphocytes T CD4+/effets des radiations , Lymphocytes T régulateurs/immunologie , Lymphocytes T régulateurs/effets des radiations , Lymphocytes T CD8+/immunologie , Lymphocytes T CD8+/effets des radiations , Antigène CTLA-4/immunologie , Mort cellulaire/immunologie , Mort cellulaire/effets des radiations , Cellules cultivées , Facteurs de transcription Forkhead/immunologie , Humains , Immunothérapie/méthodes , Activation des lymphocytes/immunologie , Activation des lymphocytes/effets des radiations , Tumeurs/immunologie , Phénotype , Rayonnement ionisant , Lymphocytes T cytotoxiques/immunologie , Lymphocytes T cytotoxiques/effets des radiations , Facteur de croissance transformant bêta-1/immunologieRÉSUMÉ
Extracorporeal photochemotherapy (ECP) that takes advantage of the immunomodulatory effects of UV light has been extensively used for many years for the treatment of several T cell-mediated diseases, including graft-versus-host disease (GvHD) and systemic scleroderma. Immune mechanisms that lead to the establishment of T cell tolerance in ECP-treated patients remain poorly known. In this study, we have tested the effect of UV/psoralen-treated BM-derived dendritic cells, referred to as ECP-BMDCs on the outcome of an antigen-specific T cell-mediated reaction, that is, contact hypersensitivity (CHS), which is mediated by CD8+ effector T cells (CD8+ Teff ). The intravenous (i.v.) injection of antigen-pulsed ECP-BMDCs in recipient C57BL/6 mice induced specific CD8+ T cells endowed with immunomodulatory properties (referred to as CD8+ TECP ), which prevented the priming of CD8+ Teff and the development of CHS, independently of conventional CD4+ regulatory T cells. CD8+ TECP mediated tolerance by inhibiting the migration and functions of skin DC and subsequently the priming of CD8+ Teff . CD8+ TECP displayed none of the phenotypes of the usual CD8+ T regulatory cells described so far. Our results reveal an underestimated participation of CD8+ T cells to ECP-induced immunomodulation that could explain the therapeutic effects of ECP in T cell-mediated diseases.
Sujet(s)
Cellules dendritiques/immunologie , Eczéma de contact/thérapie , Tolérance immunitaire , Immunomodulation/effets des radiations , Lymphocytes T cytotoxiques/effets des radiations , Lymphocytes T régulateurs/effets des radiations , Allergènes/administration et posologie , Animaux , Cellules de la moelle osseuse/cytologie , Cellules de la moelle osseuse/immunologie , Cellules dendritiques/cytologie , Cellules dendritiques/transplantation , Eczéma de contact/immunologie , Eczéma de contact/physiopathologie , 1-Fluoro-2,4-dinitro-benzène/administration et posologie , Modèles animaux de maladie humaine , Femelle , Psoralène/administration et posologie , Humains , Souris de lignée C57BL , Souris transgéniques , Photophérèse/méthodes , Photosensibilisants/administration et posologie , Lymphocytes T cytotoxiques/immunologie , Lymphocytes T cytotoxiques/anatomopathologie , Lymphocytes T régulateurs/immunologie , Lymphocytes T régulateurs/anatomopathologie , Rayons ultravioletsRÉSUMÉ
The majority of human vaccines are administered above the deltoid muscle of the arm, a site that is chronically sun-exposed in many people. It is known that exposure of the skin to the UV wavelengths in sunlight stimulates systemic immunosuppression, an outcome that is associated with reduced immunity to microbial infections in animal models. Here we consider whether immunization of humans through a UV-irradiated skin site will lead to a less effective immune response compared with immunization through an unexposed site. Studies showing that the efficacy of vaccination can be reduced when surrogates of increased levels of sun exposure, such as latitude of residence and season of the year, are considered. Results from a limited number of intervention experiments in humans demonstrate a similar pattern. To provide an explanation for these findings, changes in the number and functional potential of immune cells in chronically sun-exposed compared with unexposed skin are outlined. UV radiation-induced changes to skin cells are also relevant when considering skin sites for administration of immune-tolerizing peptides. The review provides the basis for further research into the effects of acute and chronic UV radiation exposure on skin cells in the context of vaccination.
Sujet(s)
Tolérance immunitaire/effets des radiations , Immunogénicité des vaccins , Peau/effets des radiations , Lumière du soleil , Vaccination , Vaccins/administration et posologie , Animaux , Cellules dendritiques/immunologie , Cellules dendritiques/effets des radiations , Humains , Mémoire immunologique/effets des radiations , Injections intradermiques , Mastocytes/immunologie , Mastocytes/effets des radiations , Saisons , Peau/immunologie , Lymphocytes T régulateurs/immunologie , Lymphocytes T régulateurs/effets des radiationsRÉSUMÉ
BACKGROUND: Radioresistance represents a major problem in the treatment of head and neck cancer (HNC) patients. To improve response, understanding tumor microenvironmental factors that contribute to radiation resistance is important. Regulatory T cells (Tregs) are enriched in numerous cancers and can dampen the response to radiation by creating an immune-inhibitory microenvironment. The purpose of this study was to investigate mechanisms of Treg modulation by radiation in HNC. METHODS: We utilized an orthotopic mouse model of HNC. Anti-CD25 was used for Treg depletion. Image-guided radiation was delivered to a dose of 10 Gy. Flow cytometry was used to analyze abundance and function of intratumoral immune cells. Enzyme-linked immunosorbent assay was performed to assess secreted factors. For immune-modulating therapies, anti-PD-L1, anti-CTLA-4, and STAT3 antisense oligonucleotide (ASO) were used. All statistical tests were two-sided. RESULTS: Treatment with anti-CD25 and radiation led to tumor eradication (57.1%, n = 4 of 7 mice), enhanced T-cell cytotoxicity compared with RT alone (CD4 effector T cells [Teff]: RT group mean = 5.37 [ 0.58] vs RT + αCD25 group mean =10.71 [0.67], P = .005; CD8 Teff: RT group mean = 9.98 [0.81] vs RT + αCD25 group mean =16.88 [2.49], P = .01) and induced tumor antigen-specific memory response (100.0%, n = 4 mice). In contrast, radiation alone or when combined with anti-CTLA4 did not lead to durable tumor control (0.0%, n = 7 mice). STAT3 inhibition in combination with radiation, but not as a single agent, improved tumor growth delay, decreased Tregs, myeloid-derived suppressor cells, and M2 macrophages and enhanced effector T cells and M1 macrophages. Experiments in nude mice inhibited the benefit of STAT3 ASO and radiation. CONCLUSION: We propose that STAT3 inhibition is a viable and potent therapeutic target against Tregs. Our data support the design of clinical trials integrating STAT3 ASO in the standard of care for cancer patients receiving radiation.
Sujet(s)
Tumeurs de la tête et du cou/radiothérapie , Déplétion lymphocytaire , Radioimmunothérapie/méthodes , Facteur de transcription STAT-3/antagonistes et inhibiteurs , Carcinome épidermoïde de la tête et du cou/radiothérapie , Lymphocytes T régulateurs/effets des radiations , Analyse de variance , Animaux , Cytotoxicité immunologique , Femelle , Facteurs de transcription Forkhead/génétique , Analyse de profil d'expression de gènes , Tumeurs de la tête et du cou/génétique , Tumeurs de la tête et du cou/immunologie , Humains , Mémoire immunologique , Sous-unité alpha du récepteur à l'interleukine-2/génétique , Déplétion lymphocytaire/méthodes , Macrophages/effets des radiations , Souris , Souris de lignée BALB C , Souris de lignée C57BL , Souris nude , Cellules myéloïdes suppressives/effets des radiations , Radiotolérance , Radiothérapie guidée par l'image , Facteur de transcription STAT-3/métabolisme , Carcinome épidermoïde de la tête et du cou/génétique , Carcinome épidermoïde de la tête et du cou/immunologie , Lymphocytes T régulateurs/immunologie , Lymphocytes T régulateurs/métabolisme , Facteur de croissance transformant bêta-1/génétique , Microenvironnement tumoralRÉSUMÉ
PURPOSE: The limitation of hypofractionated radiation efficacy is due partly to the immunosuppressive tumor microenvironment. Indoleamine 2,3-dioxygenase 1 (IDO1) is an important regulator of tumor immune suppression. We evaluated the effects of IDO1 in hypofractionated radiation using a Lewis lung carcinoma (LLC) mouse model and tested whether IDO1 inhibition could sensitize those tumors to hypofractionated radiation. METHODS AND MATERIALS: Bilateral LLC tumors were established in C57BL/6 mice. Primary tumors were treated with 3 fractions of either 12 Gy or 6 Gy, and the IDO1 inhibitor INCB023843 was given starting on the first day of radiation. Plasma tryptophan and kynurenine levels were quantified by liquid chromatography and tandem mass spectrometry. Tumor-infiltrating immune cells were isolated from the tumors, stained, and quantified by flow cytometry. RESULTS: The combination of INCB023843 and three 12-Gy fractions led to better tumor control and survival than radiation alone; INCB023843 plus three 6-Gy fractions had no benefit. IDO1 expression by tumor-infiltrating immune cells was increased by three 12-Gy doses and inhibited by the addition of INCB023843. Nearly all IDO1+ immune cells were also F4/80+. Percentages of IDO1+F4/80+ immune cells were drastically increased by three 12-Gy fractions and by three 6-Gy fractions, but only INCB023843 combined with three 12-Gy fractions reduced those percentages. IDO1+F4/80+ immune cells were further found to be CD11b+, Gr1-intermediate-expressing, CD206-, and CD11c- (ie, myeloid-derived suppressor cells). Three 12-Gy fractions also increased the percentages of tumor-infiltrating T regulatory cells and CD8+ T cells, but adding INCB023843 did not affect those percentages. CONCLUSIONS: In addition to its immune activation effects, hypofractionated radiation induced "rebound immune suppression" in the tumor microenvironment by activating and recruiting IDO1-expressing myeloid-derived suppressor cells in a dose-dependent manner. Adding an IDO1 inhibitor to hypofractionated radiation reduced the percentages of these cells, overcame the immune suppression, and sensitized LLC tumors to hypofractionated radiation.
Sujet(s)
Carcinome pulmonaire de Lewis/radiothérapie , Tolérance immunitaire , Indoleamine-pyrrole 2,3,-dioxygenase/antagonistes et inhibiteurs , Cellules myéloïdes suppressives/cytologie , Oximes/pharmacologie , Radiotolérance/immunologie , Sulfonamides/pharmacologie , Microenvironnement tumoral/immunologie , Animaux , Carcinome pulmonaire de Lewis/immunologie , Carcinome pulmonaire de Lewis/anatomopathologie , Indoleamine-pyrrole 2,3,-dioxygenase/métabolisme , Souris , Souris de lignée C57BL , Cellules myéloïdes suppressives/métabolisme , Hypofractionnement de dose , Lymphocytes T régulateurs/effets des médicaments et des substances chimiques , Lymphocytes T régulateurs/effets des radiations , Régulation positive/effets des radiationsRÉSUMÉ
PURPOSE: Adaptive antitumor immunity following ablative radiotherapy (ART) is attenuated by host myeloid-derived suppressor cell (MDSC), tumor-associated macrophage (TAM), and regulatory T-cell (Treg) infiltrates. We hypothesized treatment with ART and a secondary mitochondrial-derived activators of caspase (SMAC) mimetic could reverse the immunosuppressive lung cancer microenvironment to favor adaptive immunity. EXPERIMENTAL DESIGN: To evaluate for synergy between ART and the SMAC mimetic Debio 1143 and the dependence upon CD8+ T cells and TNFα, we used LLC-OVA syngeneic mouse model of lung cancer and treated them with Debio 1143 and/or ART (30 Gy) with or without anti-CD8, anti-TNFα, or anti-IFNγ antibodies. Tumor-infiltrating OVA-specific CD8+ T cells, Tc1 effector cells, MDSCs, TAMs, and Tregs, were quantified by flow cytometry. Tc1-promoting cytokines TNFα, IFNγ, and IL1ß and the immunosuppressive IL10 and Arg-1 within LLC-OVA tumor tissue or mouse serum were measured by RT-PCR and ELISA. RESULTS: ART delayed tumor growth, and the addition of Debio 1143 greatly enhanced its efficacy, which included several complete responses. These complete responders rejected an LLC-OVA tumor rechallenge. ART and Debio 1143 synergistically induced a tumor-specific, Tc1 cellular and cytokine response while eliminating immunosuppressive cells and cytokines from the tumor microenvironment. Depletion of CD8+ cells, TNFα, and IFNγ with blocking antibody abrogated synergy between ART and Debio 1143 and partially restored tumor-infiltrating MDSCs. CONCLUSIONS: Debio 1143 augments the tumor-specific adaptive immunity induced by ART, while reversing host immunosuppressive cell infiltrates in the tumor microenvironment in a TNFα, IFNγ, and CD8+ T-cell-dependent manner. This provides a novel strategy to enhance the immunogenicity of ART.
Sujet(s)
Protéines régulatrices de l'apoptose/métabolisme , Azocines/usage thérapeutique , Composés benzhydryliques/usage thérapeutique , Matériaux biomimétiques/usage thérapeutique , Carcinome pulmonaire de Lewis/thérapie , Tumeurs du poumon/thérapie , Protéines mitochondriales/métabolisme , Radiothérapie/méthodes , Animaux , Apoptose/effets des médicaments et des substances chimiques , Apoptose/immunologie , Apoptose/effets des radiations , Azocines/immunologie , Composés benzhydryliques/immunologie , Matériaux biomimétiques/métabolisme , Lymphocytes T CD8+/effets des médicaments et des substances chimiques , Lymphocytes T CD8+/immunologie , Lymphocytes T CD8+/effets des radiations , Carcinome pulmonaire de Lewis/immunologie , Carcinome pulmonaire de Lewis/anatomopathologie , Lignée cellulaire tumorale , Association thérapeutique , Cytokines/sang , Cytokines/génétique , Cytokines/immunologie , Femelle , Humains , Tumeurs du poumon/immunologie , Tumeurs du poumon/anatomopathologie , Souris de lignée C57BL , Cellules myéloïdes suppressives/immunologie , Cellules myéloïdes suppressives/métabolisme , Lymphocytes T régulateurs/effets des médicaments et des substances chimiques , Lymphocytes T régulateurs/immunologie , Lymphocytes T régulateurs/effets des radiations , Microenvironnement tumoral/effets des médicaments et des substances chimiques , Microenvironnement tumoral/immunologie , Microenvironnement tumoral/effets des radiationsRÉSUMÉ
This study investigated serum 25-hydroxyvitamin D (25(OH)D) concentrations and circulating regulatory T cells in patients with atopic dermatitis receiving narrow-band ultraviolet B (nbUVB) phototherapy. Thirty adult patients with atopic dermatitis were included. Blood samples were collected at baseline and at weeks 2 and 4 of nbUVB phototherapy. Skin biopsies were taken at baseline and at week 4. Serum 25(OH)D concentrations increased significantly following nbUVB phototherapy (estimate of change from baseline to week 2: 32.00 nmol/l, confidence interval (CI) 20.48-43.52, p < 0.0001, n = 25; and from baseline to week 4: 50.30 nmol/l, CI 37.28-63.33, p < 0.0001, n = 18). This increase was independent of the filaggrin gene FLG loss-of-function mutation status. Flow cytometry showed no significant change in regulatory T cells or cytokine profiles of T cells in blood. Real-time quantitative PCR showed no change in skin cytokine levels. In conclusion, nbUVB phototherapy was associated with increased serum 25(OH)D concentrations, but not changes in circulating regulatory T cells in patients with atopic dermatitis.
Sujet(s)
Eczéma atopique/radiothérapie , Lymphocytes T régulateurs/effets des radiations , Traitement par ultraviolets , Vitamine D/analogues et dérivés , Adulte , Marqueurs biologiques/sang , Numération des lymphocytes CD4 , Eczéma atopique/sang , Eczéma atopique/diagnostic , Eczéma atopique/immunologie , Femelle , Protéines filaggrine , Humains , Mâle , Adulte d'âge moyen , Lymphocytes T régulateurs/immunologie , Facteurs temps , Résultat thérapeutique , Vitamine D/sang , Jeune adulteRÉSUMÉ
UV radiation (UVR) causing DNA damage is a well-documented risk factor for nonmelanoma skin cancer. Although poorly understood, UVR may also indirectly contribute to carcinogenesis by promoting immune evasion. To our knowledge, we report the first epidemiological study designed to investigate the association between quantitative measures of UVR, obtained using a spectrophotometer, and circulating T regulatory (Treg) cells. In addition to total Treg cells, the proportion of functionally distinct Treg cell subsets defined by CD45RA and CD27 phenotypic markers, graded expression of FOXP3 and CD25, and those expressing cutaneous lymphocyte-associated Ag and the chemokine receptor CCR4 were enumerated in 350 individuals undergoing routine skin cancer screening exams and determined not to have prevalent skin cancer. No associations were identified for UVR exposure or the overall proportion of circulating Treg cells; however, Treg cell subpopulations with an activation-associated phenotype, CD45RA-/CD27-, and those expressing cutaneous homing receptors were significantly positively associated with UVR. These subpopulations of Treg cells also differed by age, sex, and race. After stratification by natural skin tone, and adjusting for age and sex, we found that spectrophotometer-based measures of UVR exposure, but not self-reported measures of past sun exposure, were positively correlated with the highest levels of these Treg cell subpopulations, particularly among lighter-skinned individuals. Findings from this large epidemiologic study highlight the diversity of human Treg cell subpopulations associated with UVR, thus raising questions about the specific coordinated expression of CD45RA, CD27, CCR4, and cutaneous lymphocyte-associated Ag on Treg cells and the possibility that UVR contributes to nonmelanoma skin cancer carcinogenesis through Treg cell-mediated immune evasion.
Sujet(s)
Exposition aux rayonnements/effets indésirables , Tumeurs cutanées/immunologie , Sous-populations de lymphocytes T/immunologie , Lymphocytes T régulateurs/immunologie , Rayons ultraviolets/effets indésirables , Carcinogenèse/effets des radiations , Études de cohortes , Dépistage précoce du cancer , Femelle , Facteurs de transcription Forkhead/métabolisme , Humains , Tolérance immunitaire , Immunophénotypage , Antigènes CD45/métabolisme , Mâle , Adulte d'âge moyen , Récepteurs CCR4/métabolisme , Tumeurs cutanées/épidémiologie , Phénomènes physiologiques de la peau , Pigmentation de la peau , Sous-populations de lymphocytes T/effets des radiations , Lymphocytes T régulateurs/effets des radiations , Échappement de la tumeur à la surveillance immunitaire , Antigènes CD27/métabolisme , États-Unis/épidémiologieRÉSUMÉ
Activation of T cells, a major fraction of peripheral blood lymphocytes (PBLCS), is essential for the immune response. Genotoxic stress resulting from ionizing radiation (IR) and chemical agents, including anticancer drugs, has serious impact on T cells and, therefore, on the immune status. Here we compared the sensitivity of non-stimulated (non-proliferating) vs. CD3/CD28-stimulated (proliferating) PBLC to IR. PBLCs were highly sensitive to IR and, surprisingly, stimulation to proliferation resulted in resistance to IR. Radioprotection following CD3/CD28 activation was observed in different T-cell subsets, whereas stimulated CD34+ progenitor cells did not become resistant to IR. Following stimulation, PBLCs showed no significant differences in the repair of IR-induced DNA damage compared with unstimulated cells. Interestingly, ATM is expressed at high level in resting PBLCs and CD3/CD28 stimulation leads to transcriptional downregulation and reduced ATM phosphorylation following IR, indicating ATM to be key regulator of the high radiosensitivity of resting PBLCs. In line with this, pharmacological inhibition of ATM caused radioresistance of unstimulated, but not stimulated, PBLCs. Radioprotection was also achieved by inhibition of MRE11 and CHK1/CHK2, supporting the notion that downregulation of the MRN-ATM-CHK pathway following CD3/CD28 activation results in radioprotection of proliferating PBLCs. Interestingly, the crosslinking anticancer drug mafosfamide induced, like IR, more death in unstimulated than in stimulated PBLCs. In contrast, the bacterial toxin CDT, damaging DNA through inherent DNase activity, and the DNA methylating anticancer drug temozolomide induced more death in CD3/CD28-stimulated than in unstimulated PBLCs. Thus, the sensitivity of stimulated vs. non-stimulated lymphocytes to genotoxins strongly depends on the kind of DNA damage induced. This is the first study in which the killing response of non-proliferating vs. proliferating T cells was comparatively determined. The data provide insights on how immunotherapeutic strategies resting on T-cell activation can be impacted by differential cytotoxic effects resulting from radiation and chemotherapy.
Sujet(s)
Protéines mutées dans l'ataxie-télangiectasie/immunologie , Antigène CD28/immunologie , Antigènes CD3/immunologie , Rayons gamma , Lymphocytes T cytotoxiques/immunologie , Lymphocytes T régulateurs/immunologie , Chlorométhyl cétones d'acides aminés/pharmacologie , Anticorps/pharmacologie , Protéines mutées dans l'ataxie-télangiectasie/antagonistes et inhibiteurs , Protéines mutées dans l'ataxie-télangiectasie/génétique , Antigène CD28/antagonistes et inhibiteurs , Antigène CD28/génétique , Antigènes CD3/antagonistes et inhibiteurs , Antigènes CD3/génétique , Caspases/génétique , Caspases/immunologie , Prolifération cellulaire/effets des médicaments et des substances chimiques , Prolifération cellulaire/effets des radiations , 4H-1-Benzopyran-4-ones/pharmacologie , DNA-activated protein kinase/antagonistes et inhibiteurs , DNA-activated protein kinase/génétique , DNA-activated protein kinase/immunologie , Résistance aux substances/génétique , Résistance aux substances/immunologie , Régulation de l'expression des gènes , Humains , Isoxazoles/pharmacologie , Activation des lymphocytes/effets des médicaments et des substances chimiques , Activation des lymphocytes/effets des radiations , Protéine homologue de MRE11/antagonistes et inhibiteurs , Protéine homologue de MRE11/génétique , Protéine homologue de MRE11/immunologie , Morpholines/pharmacologie , Culture de cellules primaires , Pyrazines/pharmacologie , Pyrones/pharmacologie , Radiotolérance/génétique , Radiotolérance/immunologie , Transduction du signal , Lymphocytes T cytotoxiques/cytologie , Lymphocytes T cytotoxiques/effets des médicaments et des substances chimiques , Lymphocytes T cytotoxiques/effets des radiations , Lymphocytes T régulateurs/cytologie , Lymphocytes T régulateurs/effets des médicaments et des substances chimiques , Lymphocytes T régulateurs/effets des radiations , Thiophènes/pharmacologie , Thioxanthènes/pharmacologieRÉSUMÉ
Despite the potential to cure metastatic disease, immunotherapy on its own often fails outright or early on due to tumor immune evasion. To address this obstacle, we investigated combinations of anti-GITR, anti-PD1 and radiation therapy (XRT) in our previously developed anti-PD1 resistant 344SQ non-small cell lung adenocarcinoma preclinical tumor model. We hypothesized that targeting multiple mechanisms of immune evasion with this triple therapy would lead to an enhanced tumor-specific immune response and improve survival more so than any mono- or dual therapy. In a two tumor 344SQR murine model, treatment with anti-GITR, anti-PD1, and XRT led to significantly improved survival and an abscopal response, with half of the mice becoming tumor free. These mice showed durable response and increased CD4+ and CD8+ effector memory on tumor rechallenge. Regulatory T cells (Tregs) expressed the highest level of GITR at the tumor site and anti-GITR therapy drastically diminished Tregs at the tumor site. Anti-tumor effects were largely dependent on CD4+ T cells and partially dependent on CD8+ T cells. Anti-GITR IgG2a demonstrated superior efficacy to anti-GITR IgG1 in driving antitumor effects. Collectively, these results suggest that combinatorial strategies targeting multiple points of tumor immune evasion may lead to a robust and lasting antitumor response.
Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Carcinome pulmonaire non à petites cellules/thérapie , Protéine associée au récepteur du TNF induit par les corticoïdes/antagonistes et inhibiteurs , Tumeurs du poumon/thérapie , Lymphocytes T régulateurs/immunologie , Échappement de la tumeur à la surveillance immunitaire/immunologie , Animaux , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Carcinome pulmonaire non à petites cellules/immunologie , Carcinome pulmonaire non à petites cellules/mortalité , Carcinome pulmonaire non à petites cellules/anatomopathologie , Lignée cellulaire tumorale/transplantation , Chimioradiothérapie/effets indésirables , Chimioradiothérapie/méthodes , Modèles animaux de maladie humaine , Tests de criblage d'agents antitumoraux , Protéine associée au récepteur du TNF induit par les corticoïdes/agonistes , Protéine associée au récepteur du TNF induit par les corticoïdes/immunologie , Humains , Tumeurs du poumon/immunologie , Tumeurs du poumon/mortalité , Tumeurs du poumon/anatomopathologie , Mâle , Souris , Récepteur-1 de mort cellulaire programmée/antagonistes et inhibiteurs , Récepteur-1 de mort cellulaire programmée/immunologie , Analyse de survie , Lymphocytes T régulateurs/effets des médicaments et des substances chimiques , Lymphocytes T régulateurs/effets des radiations , Résultat thérapeutique , Charge tumorale/effets des médicaments et des substances chimiques , Charge tumorale/effets des radiations , Échappement de la tumeur à la surveillance immunitaire/effets des médicaments et des substances chimiques , Échappement de la tumeur à la surveillance immunitaire/effets des radiationsRÉSUMÉ
Exposure of skin to ultraviolet (UV) radiation induces DNA damage, inflammation, and immune suppression that ultimately lead to skin cancer. However, some of the pathways that regulate these events are poorly understood. We exposed mice to UVB to study its early effects in the absence of Cbl-b, a known suppressor of antitumor immune response in the skin. Cbl-b-/- mice were protected from UV-induced cell damage as shown by the lower number of cyclobutane pyrimidine dimers and sunburn cells in exposed skin compared to wild-type mice. Microarray data revealed that deficiency of Cbl-b resulted in differential expression of genes involved in apoptosis evasion, tumor suppression and cell survival in UV-exposed skin. After UVB, Cbl-b-/- mice upregulated gene expression pattern associated with regulation of epidermal cell proliferation linked to Wnt signaling mediators and enzymes that relate to cell removal and tissue remodeling like MMP12. Additionally, the skin of Cbl-b-/- mice was protected from chronic inflammatory responses and epidermal hyperplasia in a 4-weeks UVB treatment protocol. Overall, our results suggest a novel role for Cbl-b in regulating inflammation and physiologic clearance of damaged cells in response to UVB by modulating inflammatory gene signature.
Sujet(s)
Protéines adaptatrices de la transduction du signal/génétique , Protéines proto-oncogènes c-cbl/génétique , Peau/effets des radiations , Rayons ultraviolets , Protéines adaptatrices de la transduction du signal/déficit , Animaux , Régulation de l'expression des gènes/effets des radiations , Inflammation/génétique , Inflammation/anatomopathologie , Matrix metalloproteinase 12/métabolisme , Souris , Souris de lignée C57BL , Souris knockout , Protéines proto-oncogènes c-cbl/déficit , Peau/métabolisme , Peau/anatomopathologie , Lymphocytes T régulateurs/cytologie , Lymphocytes T régulateurs/métabolisme , Lymphocytes T régulateurs/effets des radiations , bêta-Caténine/métabolismeRÉSUMÉ
In mammals, a master clock is located within the suprachiasmatic nucleus (SCN) of the hypothalamus, a region that receives input from the retina that is transmitted by the retinohypothalamic tract. The SCN controls the nocturnal synthesis of melatonin by the pineal gland that can influence the activity of the clock's genes and be involved in the inhibition of cancer development. On the other hand, in the literature, some papers highlight that artificial light exposure at night (LAN)-induced circadian disruptions promote cancer. In the present review, we summarize the potential mechanisms by which LAN-evoked disruption of the nocturnal increase in melatonin synthesis counteracts its preventive action on human cancer development and progression. In detail, we discuss: (i) the Warburg effect related to tumor metabolism modification; (ii) genomic instability associated with L1 activity; and (iii) regulation of immunity, including regulatory T cell (Treg) regulation and activity. A better understanding of these processes could significantly contribute to new treatment and prevention strategies against hormone-related cancer types.