RÉSUMÉ
Agonistic antibodies against CD137 have been demonstrated to completely regress established tumors through activating T cell immunity. Unfortunately, current CD137 antibodies failed to benefit patients with cancer. Moreover, their antitumor mechanisms in vivo remain to be determined. Here, we report the development of a small molecular CD137 agonist, JNU-0921. JNU-0921 effectively activates both human and mouse CD137 through direct binding their extracellular domains to induce oligomerization and signaling and effectively shrinks tumors in vivo. Mechanistically, JNU-0921 enhances effector and memory function of cytotoxic CD8+ T cells (CTLs) and alleviates their exhaustion. JNU-0921 also skews polarization of helper T cells toward T helper 1 type and enhances their activity to boost CTL function. Meanwhile, JNU-0921 attenuates the inhibitory function of regulatory T cells on CTLs. Our current work shows that JNU-0921 shrinks tumors by enhancing the cytotoxicity of CTLs in cis and in trans and sheds light on strategy for developing CD137 small molecular agonists.
Sujet(s)
Lymphocytes T CD8+ , Antigènes CD137 , Animaux , Antigènes CD137/agonistes , Antigènes CD137/immunologie , Humains , Souris , Lymphocytes T CD8+/immunologie , Lymphocytes T CD8+/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Lymphocytes T cytotoxiques/immunologie , Lymphocytes T cytotoxiques/effets des médicaments et des substances chimiques , Antinéoplasiques/pharmacologie , Transduction du signal/effets des médicaments et des substances chimiques , Cytotoxicité immunologique/effets des médicaments et des substances chimiques , Tests d'activité antitumorale sur modèle de xénogreffe , Tumeurs/immunologie , Tumeurs/traitement médicamenteux , Tumeurs/anatomopathologieRÉSUMÉ
Transforming growth factor ß (TGFß) is present in blood of patients who do not respond to anti-programmed cell death (ligand) 1 [PD-(L)1] treatment, and through synergy with vascular endothelial growth factor (VEGF), it helps to create an environment that promotes tumor immune evasion and immune tolerance. Therefore, simultaneous inhibition of TGFß/VEGF is more effective than targeting TGFß alone. In this study, the dual inhibitory mechanism of TU2218 was identified through in vitro analysis mimicking the tumor microenvironment, and its antitumor effects were analyzed using mouse syngeneic tumor models. TU2218 directly restored the activity of damaged cytotoxic T lymphocytes (CTLs) and natural killer cells inhibited by TGFß and suppressed the activity and viability of regulatory T cells. The inactivation of endothelial cells induced by VEGF stimulation was completely ameliorated by TU2218, an effect not observed with vactosertib, which inhibits only TGFß signaling. The combination of TU2218 and anti-PD1 therapy had a significantly greater antitumor effect than either drug alone in the poorly immunogenic B16F10 syngeneic tumor model. The mechanism of tumor reduction was confirmed by flow cytometry, which showed upregulated VCAM-1 expression in vascular cells and increased influx of CD8 + CTLs into the tumor. As another strategy, combination of anti-CTLA4 therapy and TU2218 resulted in high complete regression (CR) rates in CT26 and WEHI-164 tumor models. In particular, immunological memory generated by the combination of anti-CTLA4 and TU2218 in the CT26 model prevented the development of tumors after additional tumor cell transplantation, suggesting that the TU2218-based combination has therapeutic potential in immunotherapy.
Sujet(s)
Inhibiteurs de points de contrôle immunitaires , Récepteur de type I du facteur de croissance transformant bêta , Récepteur-2 au facteur croissance endothéliale vasculaire , Animaux , Souris , Inhibiteurs de points de contrôle immunitaires/pharmacologie , Inhibiteurs de points de contrôle immunitaires/usage thérapeutique , Récepteur de type I du facteur de croissance transformant bêta/antagonistes et inhibiteurs , Récepteur-2 au facteur croissance endothéliale vasculaire/antagonistes et inhibiteurs , Récepteur-2 au facteur croissance endothéliale vasculaire/métabolisme , Récepteur-2 au facteur croissance endothéliale vasculaire/immunologie , Humains , Microenvironnement tumoral/effets des médicaments et des substances chimiques , Microenvironnement tumoral/immunologie , Souris de lignée C57BL , Femelle , Lymphocytes T cytotoxiques/immunologie , Lymphocytes T cytotoxiques/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Facteur de croissance transformant bêta/métabolisme , Facteur de croissance transformant bêta/antagonistes et inhibiteurs , Immunothérapie/méthodesRÉSUMÉ
The antitumor strategies based on innate immunity activation have become favored by researchers in recent years. In particular, strategies targeting antiphagocytic signaling blockade to enhance phagocytosis have been widely reported. For example, the addition of prophagocytic signals such as calreticulin could make the strategy significantly more effective. In this study, an antitumor strategy that combines photodynamic therapy (PDT) with CD47 blockade has been reported. This approach promotes the maturation of dendritic cells and the presentation of tumor antigens by PDT-mediated tumor immunogenic cell death, as well as the enhancement of cytotoxic T lymphocyte infiltration in tumor areas and the phagocytic activity of phagocytes. Furthermore, the downregulation and blockage of CD47 protein could further promote phagocytic activity, strengthen the innate immune system, and ultimately elevate the antitumor efficacy and inhibit tumor metastasis.
Sujet(s)
Antigènes CD47 , Cellules dendritiques , Phagocytose , Photothérapie dynamique , Antigènes CD47/antagonistes et inhibiteurs , Antigènes CD47/métabolisme , Photothérapie dynamique/méthodes , Animaux , Souris , Phagocytose/effets des médicaments et des substances chimiques , Cellules dendritiques/effets des médicaments et des substances chimiques , Cellules dendritiques/immunologie , Lignée cellulaire tumorale , Tumeurs/traitement médicamenteux , Tumeurs/immunologie , Tumeurs/anatomopathologie , Souris de lignée C57BL , Photosensibilisants/pharmacologie , Photosensibilisants/usage thérapeutique , Humains , Lymphocytes T cytotoxiques/immunologie , Lymphocytes T cytotoxiques/effets des médicaments et des substances chimiques , Immunité innée/effets des médicaments et des substances chimiques , Souris de lignée BALB C , FemelleRÉSUMÉ
Chemo-immunotherapy holds the advantage of specific antitumor effects by activating cytotoxic lymphocyte cells (CTLs) immune response. However, multiple barriers have limited the outcomes partly due to tumor-cell-mediated exhaustion of CTLs in the immunosuppressive tumor microenvironment (iTME). Here, we rationally designed a simple-yet-versatile Ca2+ nanogenerator to modulate iTME for enhancing 2-deoxyglucose (2-DG) mediated chemo-immunotherapy. Briefly, after 2-DG chemotherapy, CaO2 nanoparticles coated with EL4 cell membrane (denoted as CaNP@ECM) could preferentially accumulate in tumor tissue via adhesion between LFA-1 on EL4 cell membrane and ICAM-1 on inflamed endothelial cell in tumor tissues and display a series of benefits for CTLs: i) Increasing glucose availability of CTLs while reducing lactic acid secretion through Ca2+ overloading mediated inhibition of tumor cell glycolysis, as well as relieving hypoxia; ii) Reversing CTLs exhaustion via TGF-ß1 scavenging and PD-L1 blockade through PD-1 and TGF-ß1R on EL4 cell membrane; iii) Boosting tumor immunotherapy via immunologic death (ICD) of tumor cells induced by Ca2+ overloading. We demonstrate that the multi-modal Ca2+ nanogenerator rescues T cells from exhaustion and inhibits tumor growth both in vitro and in vivo. More importantly, the study also facilitate the development of glucose metabolism inhibition-based tumor immunotherapy via Ca2+ overloading.
Sujet(s)
Calcium , Désoxyglucose , Immunothérapie , Souris de lignée C57BL , Nanoparticules , Microenvironnement tumoral , Animaux , Immunothérapie/méthodes , Désoxyglucose/pharmacologie , Désoxyglucose/administration et posologie , Nanoparticules/administration et posologie , Microenvironnement tumoral/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Calcium/métabolisme , Lymphocytes T cytotoxiques/immunologie , Lymphocytes T cytotoxiques/effets des médicaments et des substances chimiques , Souris , Femelle , Tumeurs/thérapie , Tumeurs/immunologie , Tumeurs/traitement médicamenteux , Oxydes , Humains , Souris de lignée BALB C , Épuisement des cellules T , Composés du calciumRÉSUMÉ
In "immune-cold" tumors, the upregulation of immunosuppressive cells and insufficient infiltration of lymphocytes contribute to the resistance against immune therapy. Herein, we have developed a dual-enzyme-like photosensitive nanozyme (PBAF) to remodel the tumor immunosuppressive microenvironment (TIME) and induce the tumor infiltration of cytotoxic T lymphocytes (CTLs). Specifically, PBAF exhibits peroxidase (POD)-like activity and glutathione oxidase (GSHOx)-like activity and can be stimulated by 750 nm laser, promoting oxidative stress at the tumor site. Consequently, this process further leads to the reconstruction of TIME in animal experiments, inducing tumor-associated macrophages (TAMs) toward the immunostimulatory M1 phenotype, eliminating myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). Simultaneously, PBAF also promotes dendritic cells (DCs) maturation to enhance CTLs infiltration into the tumor. The remodeled TIME and enhanced immune responses by PBAF demonstrate significant post-administration inhibition of recurrence and metastasis in the treatment of malignant tumors.
Sujet(s)
Immunothérapie , Microenvironnement tumoral , Animaux , Microenvironnement tumoral/effets des médicaments et des substances chimiques , Immunothérapie/méthodes , Souris , Lymphocytes T cytotoxiques/immunologie , Lymphocytes T cytotoxiques/effets des médicaments et des substances chimiques , Souris de lignée C57BL , Cellules dendritiques/immunologie , Cellules dendritiques/métabolisme , Lignée cellulaire tumorale , Photosensibilisants/pharmacologie , Photosensibilisants/usage thérapeutique , Souris de lignée BALB C , Nanoparticules/composition chimique , Femelle , Humains , Tumeurs/thérapie , Tumeurs/immunologie , Tumeurs/anatomopathologieRÉSUMÉ
Immune therapy is the new frontier of cancer treatment. Therapeutic radiation is a known inducer of immune response and can be limited by immunosuppressive mediators including cyclooxygenase-2 (COX2) that is highly expressed in aggressive triple negative breast cancer (TNBC). A clinical cohort of TNBC tumors revealed poor radiation therapeutic efficacy in tumors expressing high COX2. Herein, we show that radiation combined with adjuvant NSAID (indomethacin) treatment provides a powerful combination to reduce both primary tumor growth and lung metastasis in aggressive 4T1 TNBC tumors, which occurs in part through increased antitumor immune response. Spatial immunological changes including augmented lymphoid infiltration into the tumor epithelium and locally increased cGAS/STING1 and type I IFN gene expression were observed in radiation-indomethacin-treated 4T1 tumors. Thus, radiation and adjuvant NSAID treatment shifts "immune desert phenotypes" toward antitumor M1/TH1 immune mediators in these immunologically challenging tumors. Importantly, radiation-indomethacin combination treatment improved local control of the primary lesion, reduced metastatic burden, and increased median survival when compared with radiation treatment alone. These results show that clinically available NSAIDs can improve radiation therapeutic efficacy through increased antitumor immune response and augmented local generation of cGAS/STING1 and type I IFNs.
Sujet(s)
Protéines membranaires , Transduction du signal , Lymphocytes T cytotoxiques , Animaux , Protéines membranaires/métabolisme , Souris , Femelle , Transduction du signal/effets des médicaments et des substances chimiques , Lymphocytes T cytotoxiques/immunologie , Lymphocytes T cytotoxiques/effets des médicaments et des substances chimiques , Tumeurs du sein triple-négatives/anatomopathologie , Tumeurs du sein triple-négatives/immunologie , Tumeurs du sein triple-négatives/traitement médicamenteux , Tumeurs du sein triple-négatives/radiothérapie , Indométacine/pharmacologie , Indométacine/usage thérapeutique , Lignée cellulaire tumorale , Humains , Tumeurs du poumon/immunologie , Tumeurs du poumon/anatomopathologie , Tumeurs du poumon/traitement médicamenteux , Inhibiteurs des cyclooxygénases/pharmacologie , Inhibiteurs des cyclooxygénases/usage thérapeutique , Nucleotidyltransferases/métabolisme , Interféron de type I/métabolisme , Cyclooxygenase 2/métabolisme , Lymphocytes TIL/immunologie , Lymphocytes TIL/effets des médicaments et des substances chimiques , Souris de lignée BALB CRÉSUMÉ
Although the combination of anti-vascular strategy plus immunotherapy has emerged as the optimal first-line treatment of hepatocellular carcinoma, lack of tumor targeting leads to low antitumor efficacy and serious side effect. Here, we report an ultra-pH-sensitive nanoparticle of gambogenic acid (GNA) encapsulated by poly(ethylene glycol)-poly(2-azepane ethyl methacrylate) (PEG-PAEMA) for tumor-targeting combined therapy of anti-vascular strategy plus immunotherapy. PEG-PAEMA-GNA nanoparticle was quite stable at pH 7.4 for 30 d. In contrast, it exerted size shrinkage, charge reversal and the release of GNA at pH 6.7 within 24 h. Moreover, PEG-PAEMA-GNA significantly enhanced the anti-vascular activity, membrane-disruptive capability and pro-apoptosis when pH changed from 7.4 to 6.7. Western blot analysis exhibits that PEG-PAEMA and its GNA nanoparticle facilitated the phosphorylation of STING protein. In vivo assays show that PEG-PAEMA-GNA not only displayed much higher tumor inhibition of 92 % than 37 % of free GNA, but also inhibited tumor vasculature, promoted the maturation of dendritic cells and recruited more cytotoxic t-lymphocytes for sufficient anti-vascular therapy and immunotherapy. All these results demonstrate that PEG-PAEMA-GNA displayed tumor-targeting combined treatment of anti-vascular therapy and immunotherapy. This study offers a simple and novel method for the combination of anti-vascular therapy and immunotherapy with high selectivity towards tumor.
Sujet(s)
Immunothérapie , Nanoparticules , Polyéthylène glycols , Xanthènes , Animaux , Immunothérapie/méthodes , Nanoparticules/composition chimique , Concentration en ions d'hydrogène , Polyéthylène glycols/composition chimique , Polyéthylène glycols/administration et posologie , Xanthènes/composition chimique , Xanthènes/administration et posologie , Xanthènes/pharmacologie , Lignée cellulaire tumorale , Humains , Souris , Apoptose/effets des médicaments et des substances chimiques , Carcinome hépatocellulaire/thérapie , Carcinome hépatocellulaire/traitement médicamenteux , Tumeurs du foie/thérapie , Tumeurs du foie/traitement médicamenteux , Souris de lignée C57BL , Cellules dendritiques/effets des médicaments et des substances chimiques , Cellules dendritiques/immunologie , Souris de lignée BALB C , Xanthones/composition chimique , Xanthones/administration et posologie , Xanthones/pharmacologie , Libération de médicament , Cellules endothéliales de la veine ombilicale humaine , Lymphocytes T cytotoxiques/immunologie , Lymphocytes T cytotoxiques/effets des médicaments et des substances chimiquesRÉSUMÉ
Triple-negative breast cancer (TNBC) is a relatively "cold" tumour with low immunogenicity compared to other tumour types. Especially, the immune checkpoint inhibitors to treat metastatic TNBC only shows the modest immune response rates. Here, we used Chlorella vulgaris as a bioreactor to synthesize an efficient nanobomb (Bio-MnSe) aimed at eliciting systemic anti-tumour immune response. Despite possessing extremely low Mn content, Bio-MnSe effectively produced more ROS and activated stronger cGAS-STING signal pathway compared to pure Se nanoparticles and free Mn2+ ions, promoting the infiltration of natural killer (NK) cells, cytotoxic T lymphocytes (CTLs) in tumour, effectively turning "cold" tumour into "hot" tumour, and achieving strong antitumour immunotherapy. Additionally, the use of αPD-L1 as an immune checkpoint antagonist further increased the anti-tumour immune response of Bio-MnSe, resulting in enhanced anti-tumour effects. Doxorubicin (Dox), an immunogenic cell death (ICD) inducer, was combined with Bio-MnSe to form Bio-MnSe@Dox. This Bio-MnSe@Dox not only directly damaged tumour cells and induced tumour ICD but also promoted dendritic cell maturation, cytotoxic T lymphocyte infiltration, and NK cell recruitment, synergistically intensifying anti-tumour immune responses and suppressing tumour relapse and lung metastasis. Collectively, our findings propose an effective strategy for transforming 'cold' tumours to 'hot' ones, thereby advancing the development of anti-tumour immune drugs. STATEMENT OF SIGNIFICANCE: A biogenic MnSe (Bio-MnSe) nanocomposite was synthesized using Chlorella vulgaris as a bioreactor for enhanced immunotherapy of TNBC. Bio-MnSe demonstrated a stronger ability to activate the cGAS-STING signalling pathway and generate more ROS compared to pure Se nanoparticles and free Mn2+ ions. Apoptotic cells induced by Bio-MnSe released a significant amount of interferon, leading to the activation of T and natural killer (NK) cells, ultimately transforming immunologically 'cold' breast tumours to 'hot' tumours and enhancing the tumour's response to immune checkpoint inhibitors. The combination of Bio-MnSe with Dox or αPD-L1 further enhanced the anti-tumour immune response, fostering dendritic cell maturation, infiltration of cytotoxic T lymphocytes, and recruitment of NK cells, thereby enhancing the anti-tumour immunotherapy of TNBC.
Sujet(s)
Mort cellulaire immunogène , Manganèse , Protéines membranaires , Nucleotidyltransferases , Transduction du signal , Animaux , Femelle , Mort cellulaire immunogène/effets des médicaments et des substances chimiques , Souris , Humains , Lignée cellulaire tumorale , Transduction du signal/effets des médicaments et des substances chimiques , Nucleotidyltransferases/métabolisme , Protéines membranaires/métabolisme , Manganèse/composition chimique , Manganèse/pharmacologie , Doxorubicine/pharmacologie , Tumeurs du sein triple-négatives/anatomopathologie , Tumeurs du sein triple-négatives/immunologie , Tumeurs du sein triple-négatives/traitement médicamenteux , Sélénium/composition chimique , Sélénium/pharmacologie , Immunothérapie/méthodes , Cellules tueuses naturelles/immunologie , Cellules tueuses naturelles/effets des médicaments et des substances chimiques , Cellules tueuses naturelles/métabolisme , Nanoparticules/composition chimique , Espèces réactives de l'oxygène/métabolisme , Antigène CD274/métabolisme , Souris de lignée BALB C , Lymphocytes T cytotoxiques/immunologie , Lymphocytes T cytotoxiques/effets des médicaments et des substances chimiquesRÉSUMÉ
Treatment of advanced triple-negative breast cancer (TNBC) is a great challenge in clinical practice. The immune checkpoints are a category of immunosuppressive molecules that cancer could hijack and impede anti-tumor immunity. Targeting immune checkpoints, such as anti-programmed cell death 1 (PD-1) therapy, is a promising therapeutic strategy in TNBC. The efficacy and safety of PD-1 monoclonal antibody (mAb) with chemotherapy have been validated in TNBC patients. However, the precise mechanisms underlying the synergistic effect of chemotherapy and anti-PD-1 therapy have not been elucidated, causing the TNBC patients that might benefit from this combination regimen not to be well selected. In the present work, we found that IL-23, an immunological cytokine, is significantly upregulated after chemotherapy in TNBC cells and plays a vital role in enhancing the anti-tumor immune response of cytotoxic T cells (CTLs), especially in combination with PD-1 mAb. In addition, the combination of IL-23 and PD-1 mAb could synergistically inhibit the expression of Phosphoinositide-3-Kinase Regulatory Subunit 1 (PIK3R1), which is a regulatory subunit of PI3K and inhibit p110 activity, and promote phosphorylation of AKT in TNBC-specific CTLs. Our findings might provide a molecular marker that could be used to predict the effects of combination chemotherapy therapy and PD-1 mAb in TNBC.
Sujet(s)
Sous-unité p19 de l'interleukine-23 , Phosphatidylinositol 3-kinases , Récepteur-1 de mort cellulaire programmée , Protéines proto-oncogènes c-akt , Transduction du signal , Lymphocytes T cytotoxiques , Tumeurs du sein triple-négatives , Humains , Protéines proto-oncogènes c-akt/métabolisme , Tumeurs du sein triple-négatives/traitement médicamenteux , Tumeurs du sein triple-négatives/métabolisme , Tumeurs du sein triple-négatives/immunologie , Transduction du signal/effets des médicaments et des substances chimiques , Phosphatidylinositol 3-kinases/métabolisme , Récepteur-1 de mort cellulaire programmée/métabolisme , Lignée cellulaire tumorale , Femelle , Lymphocytes T cytotoxiques/effets des médicaments et des substances chimiques , Lymphocytes T cytotoxiques/immunologie , Lymphocytes T cytotoxiques/métabolisme , Sous-unité p19 de l'interleukine-23/métabolisme , Animaux , Souris , Anticorps monoclonaux/pharmacologieRÉSUMÉ
Currently, sonodynamic therapy (SDT) has limited therapeutic outcomes and immune responses, highlighting the urgent need for enhanced strategies that can stimulate robust and long-lasting antitumor effects. Microcystis, a notorious microalga, reveals the possibility of mediating SDT owing to the presence of gas vesicles (GVs) and phycocyanin (PC). Herein, a nontoxic strain of Microcystis elabens (labeled Me) is developed as a novel agent for SDT because it generates O2 under red light (RL) illumination, while GVs and PC act as cavitation nuclei and sonosensitizers, respectively. Moreover, algal debris is released after ultrasound (US) irradiation, which primes the Toll-like receptor pathway to initiate a cascade of immune responses. This sono-immune strategy inhibits CT26 colon tumor growth largely by promoting dendritic cell (DC) maturation and cytotoxic T-cell activation. After combination with the immune checkpoint blockade (ICB), the therapeutic outcome is further amplified, accompanied by satisfactory abscopal and immune memory effects; the similar potency is proven in the "cold" 4T1 triple-negative breast tumor. In addition, Me exhibits good biosafety without significant acute or chronic toxicity. Briefly, this study turns waste into wealth by introducing sono-immunotherapy based on Microcystis that achieved encouraging therapeutic effects on cancer, which is expected to be translated into the clinic.
Sujet(s)
Microcystis , Animaux , Souris , Lignée cellulaire tumorale , Ultrasonothérapie/méthodes , Cellules dendritiques/effets des médicaments et des substances chimiques , Cellules dendritiques/immunologie , Humains , Phycocyanine/composition chimique , Phycocyanine/pharmacologie , Immunothérapie , Lymphocytes T cytotoxiques/immunologie , Lymphocytes T cytotoxiques/effets des médicaments et des substances chimiques , Tumeurs du côlon/thérapie , Tumeurs du côlon/immunologieRÉSUMÉ
BACKGROUND: Despite the success of antiretroviral therapy (ART), people living with HIV (PLWH) suffer from a high burden of pulmonary diseases, even after accounting for their smoking status. Cytotoxic CD8 T-cells are likely implicated in this phenomenon and may act as a double-edged sword. While being essential in viral infection control, their hyperactivation can also contribute to lung mucosal tissue damage. The effects of HIV and smoking on pulmonary mucosal CD8 T-cell dynamics has been a neglected area of research, which we address herein. METHODS: Bronchoalveolar lavage (BAL) fluid were obtained from ART-treated PLWH (median duration of supressed viral load: 9 years; smokers: n = 14; non-smokers: n = 21) and HIV-uninfected controls (smokers: n = 11; non-smokers: n = 20) without any respiratory symptoms or active infection. Lymphocytes were isolated and CD8 T-cell subsets and homing markers were characterized by multiparametric flow cytometry. RESULTS: Both smoking and HIV infection were independently associated with a significant increase in frequencies of total pulmonary mucosal CD8 T-cell. BAL CD8 T-cells were primarily CD69 + expressing CD103 and/or CD49a, at least one of the two granzymes (GzmA/GzmB), and little Perforin. Higher expression levels of CD103, CD69, and GzmB were observed in smokers versus non-smokers. The ex vivo phenotype of GzmA + and GzmB + cells revealed increased expression of CD103 and CXCR6 in smokers, while PLWH displayed elevated levels of CX3CR1 compared to controls. CONCLUSION: Smoking and HIV could promote cytotoxic CD8 T-cell retention in small airways through different mechanisms. Smoking likely increases recruitment and retention of GzmB + CD8 Trm via CXCR6 and CD103. Heightened CX3CR1 expression could be associated with CD8 non-Trm recruitment from the periphery in PLWH.
Sujet(s)
Infections à VIH , Humains , Mâle , Infections à VIH/traitement médicamenteux , Infections à VIH/immunologie , Femelle , Adulte d'âge moyen , Adulte , Muqueuse respiratoire/immunologie , Muqueuse respiratoire/métabolisme , Muqueuse respiratoire/effets des médicaments et des substances chimiques , Lymphocytes T CD8+/immunologie , Lymphocytes T CD8+/effets des médicaments et des substances chimiques , Lymphocytes T CD8+/métabolisme , Lymphocytes T cytotoxiques/immunologie , Lymphocytes T cytotoxiques/effets des médicaments et des substances chimiques , Lymphocytes T cytotoxiques/métabolisme , Fumer/effets indésirables , Liquide de lavage bronchoalvéolaire/immunologie , Antirétroviraux/usage thérapeutique , Agents antiVIH/usage thérapeutique , Poumon/immunologie , Poumon/effets des médicaments et des substances chimiques , Poumon/métabolismeRÉSUMÉ
The activation of sequential events in the cancer-immunity cycle (CIC) is crucial for achieving effective antitumor immunity. However, formidable challenges, such as innate and adaptive immune resistance, along with the off-target adverse effects of nonselective immunomodulators, persist. In this study, a tumor-selective nano-regulator named PNBJQ has been presented, focusing on targeting two nonredundant immune nodes: inducing immunogenic cancer cell death and abrogating immune resistance to fully activate endogenous tumor immunity. PNBJQ is obtained by encapsulating the immunomodulating agent JQ1 within a self-assembling system formed by linking a Type-I photosensitizer to polyethylene glycol through a hypoxia-sensitive azo bond. Benefiting from the Type-I photosensitive mechanism, PNBJQ triggers the immunogenic cell death of hypoxic tumors under near-infrared (NIR) light irradiation. This process resolves innate immune resistance by stimulating sufficient cytotoxic T-lymphocytes. Simultaneously, PNBJQ smartly responds to the hypoxic tumor microenvironment for precise drug delivery, adeptly addressing adaptive immune resistance by using JQ1 to downregulate programmed death ligand 1 (PD-L1) and sustaining the response of cytotoxic T lymphocytes. The activatable synergic photoimmunotherapy promotes an immune-promoting tumor microenvironment by activating an iterative revolution of the CIC, which remarkably eradicates established hypoxic tumors and suppresses distal lesions under low light dose irradiation.
Sujet(s)
Nanoparticules , Photosensibilisants , Animaux , Souris , Lignée cellulaire tumorale , Photosensibilisants/composition chimique , Photosensibilisants/pharmacologie , Photosensibilisants/usage thérapeutique , Nanoparticules/composition chimique , Microenvironnement tumoral/effets des médicaments et des substances chimiques , Triazoles/composition chimique , Triazoles/pharmacologie , Humains , Tumeurs/traitement médicamenteux , Tumeurs/immunologie , Tumeurs/thérapie , Tumeurs/anatomopathologie , Immunothérapie , Azépines/composition chimique , Azépines/pharmacologie , Polyéthylène glycols/composition chimique , Hypoxie tumorale/effets des médicaments et des substances chimiques , Lymphocytes T cytotoxiques/immunologie , Lymphocytes T cytotoxiques/effets des médicaments et des substances chimiques , Antigène CD274/métabolisme , Rayons infrarougesRÉSUMÉ
Tumor vaccine, which can effectively prevent tumor recurrence and metastasis, is a promising tool in tumor immunotherapy. However, heterogeneity of tumors and the inability to achieve a cascade effect limit the therapeutic effects of most developing tumor vaccine. We have developed a cascading immunoinducible in-situ mannose-functionalized polydopamine loaded with imiquimod phenylboronic hyaluronic acid nanocomposite gel vaccine (M/P-PDA@IQ PHA) through a boronic ester-based reaction. This reaction utilizes mannose-functionalized polydopamine loaded with imiquimod (M/P-PDA@IQ NAs) as a cross-linking agent to react with phenylboronic-grafted hyaluronic acid. Under near-infrared light irradiation, the M/P-PDA@IQ PHA caused local hyperthermia to trigger immunogenic cell death of tumor cells and tumor-associated antigens (TAAs) releasing. Subsequently, the M/P-PDA@IQ NAs which were gradually released by the pH/ROS/GSH-triggered degradation of M/P-PDA@IQ PHA, could capture and deliver these TAAs to lymph nodes. Finally, the M/P-PDA@IQ NAs facilitated maturation and cross-presentation of dendritic cells, as well as activation of cytotoxic T lymphocytes. Overall, the M/P-PDA@IQ PHA could serve as a novel in situ vaccine to stimulate several key nodes including TAAs release and capture, targeting lymph nodes and enhanced dendritic cells uptake and maturation as well as T cells activation. This cascading immune activation strategy can effectively elicit antitumor immune response.
Sujet(s)
Vaccins anticancéreux , Acide hyaluronique , Hydrogels , Indoles , Nanoparticules , Polymères , Acide hyaluronique/composition chimique , Polymères/composition chimique , Vaccins anticancéreux/composition chimique , Vaccins anticancéreux/immunologie , Indoles/composition chimique , Indoles/pharmacologie , Animaux , Souris , Hydrogels/composition chimique , Nanoparticules/composition chimique , Humains , Imiquimod/composition chimique , Imiquimod/pharmacologie , Cellules dendritiques/immunologie , Vaccination , Lignée cellulaire tumorale , Immunothérapie/méthodes , Réactifs réticulants/composition chimique , Tumeurs/immunologie , Tumeurs/thérapie , Lymphocytes T cytotoxiques/immunologie , Lymphocytes T cytotoxiques/effets des médicaments et des substances chimiquesRÉSUMÉ
BACKGROUND AND OBJECTIVES: The role of B cells in the pathogenic events leading to relapsing multiple sclerosis (R-MS) has only been recently elucidated. A pivotal step in defining this role has been provided by therapeutic efficacy of anti-CD20 monoclonal antibodies. Indeed, treatment with anti-CD20 can also alter number and function of other immune cells not directly expressing CD20 on their cell surface, whose activities can contribute to unknown aspects influencing therapeutic efficacy. We examined the phenotype and function of cytotoxic lymphocytes and Epstein-Barr virus (EBV)-specific immune responses in people with R-MS before and after ocrelizumab treatment. METHODS: In this prospective study, we collected blood samples from people with R-MS (n = 41) before and 6 and 12 months after initiating ocrelizumab to assess the immune phenotype and the indirect impact on cytotoxic functions of CD8+ T and NK cells. In addition, we evaluated the specific anti-EBV proliferative responses of both CD8+ T and NK lymphocytes as surrogate markers of anti-EBV activity. RESULTS: We observed that while ocrelizumab depleted circulating B cells, it also reduced the expression of activation and migratory markers on both CD8+ T and NK cells as well as their in vitro cytotoxic activity. A comparable pattern in the modulation of immune molecules by ocrelizumab was observed in cytotoxic cells even when patients with R-MS were divided into groups based on their prior disease-modifying treatment. These effects were accompanied by a significant and selective reduction of CD8+ T-cell proliferation in response to EBV antigenic peptides. DISCUSSION: Taken together, our findings suggest that ocrelizumab-while depleting B cells-affects the cytotoxic function of CD8+ and NK cells, whose reduced cross-activity against myelin antigens might also contribute to its therapeutic efficacy during MS.
Sujet(s)
Anticorps monoclonaux humanisés , Lymphocytes T CD8+ , Herpèsvirus humain de type 4 , Facteurs immunologiques , Humains , Anticorps monoclonaux humanisés/pharmacologie , Femelle , Adulte , Mâle , Herpèsvirus humain de type 4/immunologie , Lymphocytes T CD8+/effets des médicaments et des substances chimiques , Lymphocytes T CD8+/immunologie , Adulte d'âge moyen , Facteurs immunologiques/pharmacologie , Sclérose en plaques récurrente-rémittente/traitement médicamenteux , Sclérose en plaques récurrente-rémittente/immunologie , Sclérose en plaques récurrente-rémittente/sang , Lymphocytes T cytotoxiques/effets des médicaments et des substances chimiques , Lymphocytes T cytotoxiques/immunologie , Études prospectives , Prolifération cellulaire/effets des médicaments et des substances chimiques , Cellules tueuses naturelles/effets des médicaments et des substances chimiques , Cellules tueuses naturelles/immunologie , Activation des lymphocytes/effets des médicaments et des substances chimiquesRÉSUMÉ
Vaccines represent one of the most powerful and cost-effective innovations for controlling a wide range of infectious diseases caused by various viruses and bacteria. Unlike mRNA and DNA-based vaccines, subunit vaccines carry no risk of insertional mutagenesis and can be lyophilized for convenient transportation and long-term storage. However, existing adjuvants are often associated with toxic effect and reactogenicity, necessitating expanding the repertoire of adjuvants with better biocompatibility, for instance, designing self-adjuvating polymeric carriers. We herein report a novel subunit vaccine delivery platform constructed via in situ free radical polymerization of C7A (2-(Hexamethyleneimino) ethyl methacrylate) and acrylamide around the surface of individual protein antigens. Using ovalbumin (OVA) as a model antigen, we observed substantial increases in both diameter (â¼70 nm) and surface potential (-1.18 mV) following encapsulation, referred to as n(OVA)C7A. C7A's ultra pH sensitivity with a transition pH around 6.9 allows for rapid protonation in acidic environments. This property facilitates crucial processes such as endosomal escape and major histocompatibility complex (MHC)-I-mediated antigen presentation, culminating in the substantial CD8+ T cell activation. Additionally, compared to OVA nanocapsules without the C7A components and native OVA without modifications, we observed heightened B cell activation within the germinal center, along with remarkable increases in serum antibody and cytokine production. It's important to note that mounting evidence suggests that adjuvant effects, particularly its targeted stimulation of type I interferons (IFNs), can contribute to advantageous adaptive immune responses. Beyond its exceptional potency, the nanovaccine also demonstrated robust formation of immune memory and exhibited a favorable biosafety profile. These findings collectively underscore the promising potential of our nanovaccine in the realm of immunotherapy and vaccine development.
Sujet(s)
Souris de lignée C57BL , Ovalbumine , Lymphocytes T cytotoxiques , Animaux , Ovalbumine/immunologie , Ovalbumine/administration et posologie , Lymphocytes T cytotoxiques/immunologie , Lymphocytes T cytotoxiques/effets des médicaments et des substances chimiques , Adjuvants immunologiques/administration et posologie , Adjuvants immunologiques/pharmacologie , Adjuvants immunologiques/composition chimique , Femelle , Méthacrylates/composition chimique , Polymères/composition chimique , Polymères/administration et posologie , Nanoparticules/composition chimique , Nanoparticules/administration et posologie , Souris , Vaccins/administration et posologie , Vaccins/immunologie , Vaccins sous-unitaires/administration et posologie , Vaccins sous-unitaires/immunologie ,RÉSUMÉ
Immunosuppression caused by incomplete radiofrequency ablation (iRFA) is a crucial factor affecting the effectiveness of RFA for solid tumors. However, little is known about the changes iRFA induces in the tumor immune microenvironment (TIME) of hepatocellular carcinoma (HCC), the primary application area for RFA. In this study, we found iRFA promotes a suppressive TIME in residual HCC tumors, characterized by M2 macrophage polarization, inhibited antigen presentation by dendritic cells (DCs), and reduced infiltration of cytotoxic T lymphocytes (CTLs). Interestingly, the STING agonist MSA-2 was able to reorganize M2-like tumor-promoting macrophages into M1-like anti-tumor states and enhance antigen presentation by DCs. To optimize the therapeutic effect of MSA-2, we used a calcium ion (Ca2+) responsive sodium alginate (ALG) as a carrier, forming an injectable hydrogel named ALG@MSA-2. This hydrogel can change from liquid to gel, maintaining continuous drug release in situ. Our results suggested that ALG@MSA-2 effectively activated anti-tumor immunity, as manifested by increased M1-like macrophage polarization, enhanced antigen presentation by DCs, increased CTL infiltration, and inhibited residual tumor growth. ALG@MSA-2 also resulted in a complete regression of contralateral tumors and widespread liver metastases in vivo. In addition, the excellent biosafety of ALG@MSA-2 was also proved by blood biochemical analysis and body weight changes in mice. In summary, this study demonstrated that the immune cascade of ALG@MSA-2 mediated the STING pathway activation and promoted a favorable TIME which might provide novel insights for the RFA treatment of HCC.
Sujet(s)
Alginates , Carcinome hépatocellulaire , Hydrogels , Tumeurs du foie , Protéines membranaires , Souris de lignée C57BL , Ablation par radiofréquence , Animaux , Carcinome hépatocellulaire/traitement médicamenteux , Carcinome hépatocellulaire/immunologie , Carcinome hépatocellulaire/thérapie , Tumeurs du foie/traitement médicamenteux , Tumeurs du foie/immunologie , Tumeurs du foie/thérapie , Hydrogels/administration et posologie , Ablation par radiofréquence/méthodes , Alginates/composition chimique , Alginates/administration et posologie , Cellules dendritiques/effets des médicaments et des substances chimiques , Cellules dendritiques/immunologie , Lignée cellulaire tumorale , Macrophages/effets des médicaments et des substances chimiques , Macrophages/immunologie , Microenvironnement tumoral/effets des médicaments et des substances chimiques , Souris , Mâle , Lymphocytes T cytotoxiques/effets des médicaments et des substances chimiques , Lymphocytes T cytotoxiques/immunologie , HumainsRÉSUMÉ
BACKGROUND: Dendritic cells (DCs) are a key class of immune cells that migrate to the draining lymph nodes and present processed antigenic peptides to lymphocytes after being activated by external stimuli, thereby establishing adaptive immunity. Moreover, DCs play an important role in tumor immunity. OBJECTIVES: The aim of the study was to investigate whether MCT1 gene silencing in DCs affects their ability to mount an immune response against cervical cancer cells. MATERIAL AND METHODS: We silenced the expression of MCT1 in DCs from mouse bone marrow (BM) by infection with adenovirus. The surface antigen profile of DCs was analyzed by flow cytometry and cytokine secretion was evaluated using enzyme-linked immunosorbent assay (ELISA) following sodium lactate (sLA) exposure and lipopolysaccharide (LPS) stimulation. Then, various groups of DC-induced cytotoxic T lymphocytes (CTLs) were prepared and their cytotoxicity against U14 was tested. RESULTS: Without sLA exposure, silencing MCT1 did not affect the expression of CD1a, CD80, CD83, CD86, and major histocompatibility complex class II (MHCII) in DCs after LPS challenge. Similar results were found for interleukin (IL)-6, IL-12 p70 and tumor necrosis factor alpha (TNF-α). After sLA exposure, silencing MCT1 significantly decreased the expression of CD1a, CD80, CD83, CD86, and MHCII in DCs after the LPS challenge, as well as the secretion of IL-6, IL-12 p70 and TNF-α. In addition, sLA exposure significantly reduced the toxicity and inhibited the proliferation of DC-induced CTLs compared to U14 cells in vitro and in vivo. However, silencing MCT1 significantly attenuated the changes caused by sLA exposure. At the same time, in the absence of sLA, silencing MCT1 did not affect the toxicity nor inhibit the proliferation of DC-induced CTLs on U14 cells. CONCLUSIONS: Lactate exposure reduces the immune effect of DCs on cervical cancer cells, but MCT1 gene silencing attenuates these alterations.
Sujet(s)
Cellules dendritiques , Extinction de l'expression des gènes , Transporteurs d'acides monocarboxyliques , Symporteurs , Tumeurs du col de l'utérus , Cellules dendritiques/immunologie , Cellules dendritiques/métabolisme , Cellules dendritiques/effets des médicaments et des substances chimiques , Tumeurs du col de l'utérus/immunologie , Tumeurs du col de l'utérus/génétique , Transporteurs d'acides monocarboxyliques/génétique , Femelle , Animaux , Symporteurs/génétique , Lignée cellulaire tumorale , Souris , Cytokines/métabolisme , Lymphocytes T cytotoxiques/immunologie , Lymphocytes T cytotoxiques/effets des médicaments et des substances chimiques , Humains , Souris de lignée C57BLRÉSUMÉ
T-cell-engaging bispecific antibody (T-BsAb, also known as BiTE) therapy has emerged as a powerful therapeutic modality against multiple myeloma. Given that T-BsAb therapy redirects endogenous T cells to eliminate tumor cells, reinvigorating dysfunctional T cells may be a potential approach to improve the efficacy of T-BsAb. While various immunostimulatory cytokines can potentiate effector T-cell functions, the optimal cytokine treatment for T-BsAb therapy is yet to be established, partly due to a concern of cytokine release syndrome driven by aberrant interferon (IFN)-γ production. Here, we functionally screen immunostimulatory cytokines to determine an ideal combination partner for T-BsAb therapy. This approach reveals interleukin (IL)-21 as a potential immunostimulatory cytokine with the ability to augment T-BsAb-mediated release of granzyme B and perforin, without increasing IFN-γ release. Transcriptome profiling and functional characterization strongly support that IL-21 selectively targets the cytotoxic granule exocytosis pathway, but not pro-inflammatory responses. Notably, IL-21 modulates multiple steps of cytotoxic effector functions including upregulation of co-activating CD226 receptor, increasing cytotoxic granules, and promoting cytotoxic granule delivery at the immunological synapse. Indeed, T-BsAb-mediated myeloma killing is cytotoxic granule-dependent, and IL-21 priming significantly augments cytotoxic activities. Furthermore, in vivo IL-21 treatment induces cytotoxic effector reprogramming in bone marrow T cells, showing synergistic anti-myeloma effects in combination with T-BsAb therapy. Together, harnessing the cytotoxic granule exocytosis pathway by IL-21 may be a potential approach to achieve better responses by T-BsAb therapy.
Sujet(s)
Anticorps bispécifiques , Exocytose , Myélome multiple , Anticorps bispécifiques/pharmacologie , Anticorps bispécifiques/usage thérapeutique , Humains , Souris , Animaux , Myélome multiple/immunologie , Myélome multiple/traitement médicamenteux , Myélome multiple/thérapie , Myélome multiple/anatomopathologie , Cytotoxicité immunologique , Interleukines/métabolisme , Lignée cellulaire tumorale , Cytokines/métabolisme , Lymphocytes T cytotoxiques/immunologie , Lymphocytes T cytotoxiques/effets des médicaments et des substances chimiques , Granzymes/métabolisme , Lymphocytes T/immunologie , Lymphocytes T/métabolisme , Lymphocytes T/effets des médicaments et des substances chimiquesRÉSUMÉ
CD8+ cytotoxic T cells (CTLs) orchestrate antitumour immunity and exhibit inherent heterogeneity1,2, with precursor exhausted T (Tpex) cells but not terminally exhausted T (Tex) cells capable of responding to existing immunotherapies3-7. The gene regulatory network that underlies CTL differentiation and whether Tex cell responses can be functionally reinvigorated are incompletely understood. Here we systematically mapped causal gene regulatory networks using single-cell CRISPR screens in vivo and discovered checkpoints for CTL differentiation. First, the exit from quiescence of Tpex cells initiated successive differentiation into intermediate Tex cells. This process is differentially regulated by IKAROS and ETS1, the deficiencies of which dampened and increased mTORC1-associated metabolic activities, respectively. IKAROS-deficient cells accumulated as a metabolically quiescent Tpex cell population with limited differentiation potential following immune checkpoint blockade (ICB). Conversely, targeting ETS1 improved antitumour immunity and ICB efficacy by boosting differentiation of Tpex to intermediate Tex cells and metabolic rewiring. Mechanistically, TCF-1 and BATF are the targets for IKAROS and ETS1, respectively. Second, the RBPJ-IRF1 axis promoted differentiation of intermediate Tex to terminal Tex cells. Accordingly, targeting RBPJ enhanced functional and epigenetic reprogramming of Tex cells towards the proliferative state and improved therapeutic effects and ICB efficacy. Collectively, our study reveals that promoting the exit from quiescence of Tpex cells and enriching the proliferative Tex cell state act as key modalities for antitumour effects and provides a systemic framework to integrate cell fate regulomes and reprogrammable functional determinants for cancer immunity.
Sujet(s)
Différenciation cellulaire , Clustered regularly interspaced short palindromic repeats , Édition de gène , Mutagenèse , Tumeurs , Analyse sur cellule unique , Lymphocytes T cytotoxiques , Humains , Différenciation cellulaire/effets des médicaments et des substances chimiques , Différenciation cellulaire/génétique , Clustered regularly interspaced short palindromic repeats/génétique , Inhibiteurs de points de contrôle immunitaires/immunologie , Inhibiteurs de points de contrôle immunitaires/pharmacologie , Tumeurs/génétique , Tumeurs/immunologie , Analyse sur cellule unique/méthodes , Lymphocytes T cytotoxiques/cytologie , Lymphocytes T cytotoxiques/effets des médicaments et des substances chimiques , Lymphocytes T cytotoxiques/immunologie , Lymphocytes T cytotoxiques/métabolismeRÉSUMÉ
Adjuvants are an indispensable component of vaccines, but there are few adjuvants for human vaccines. H2 receptor blockers, inhibiting gastric acid secretion, have immune enhancement effects. Ranitidine (RAN) is a water-soluble H2 receptor blocker, and whether it has an immune-enhancing effect is still unknown. In this study, flow cytometry, western blotting, and immunofluorescence methods were used to analyze whether RAN could activate macrophage polarization to the M1 phenotype in vivo and in vitro. Here, we found that the M1 inflammatory cytokine levels and surface markers in RAW264.7 cells were upregulated by NF-κB activation, possibly through the PI3K-Akt2 signaling pathway, after RAN treatment. Endocytic function was also enhanced by feedback regulation of Akt2/GSK3ß/Dynmin1 signaling. Furthermore, to evaluate the adjuvant function of RAN, we used OVA plus RAN as a vaccine to inhibit the growth of B16-OVA tumors in mice. We also found that in the RAN adjuvant group, macrophage polarization to M1, Th1 cell differentiation, and cytotoxic T lymphocyte (CTL) activation were significantly upregulated. The tumor growth of mice was inhibited, and the survival rate of mice was significantly improved. This study provides new evidence for the mechanism by which RAN activates the immune response and is expected to provide a new strategy for the research and development of tumor vaccine adjuvants.