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1.
Eur J Immunol ; 51(5): 1206-1217, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33555624

RESUMEN

Plasticity between Th17 and Treg cells is regarded as a crucial determinant of tumor-associated immunosuppression. Classically Th17 cells mediate inflammatory responses through production of cytokine IL17. Recently, Th17 cells have also been shown to acquire suppressive phenotypes in tumor microenvironment. However, the mechanism by which they acquire such immunosuppressive properties is still elusive. Here, we report that in tumor microenvironment Th17 cell acquires immunosuppressive properties by expressing Treg lineage-specific transcription factor FOXP3 and ectonucleotidase CD73. We designate this cell as Th17reg cell and perceive that such immunosuppressive property is dependent on CD73. It was observed that in classical Th17 cell, GFI1 recruits HDAC1 to change the euchromatin into tightly-packed heterochromatin at the proximal-promoter region of CD73 to repress its expression. Whereas in Th17reg cells GFI1 cannot get access to CD73-promoter due to heterochromatin state at its binding site and, thus, cannot recruit HDAC1, failing to suppress the expression of CD73.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , Histona Desacetilasa 1/metabolismo , Inmunomodulación , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Factores de Transcripción/metabolismo , 5'-Nucleotidasa/metabolismo , Citocinas/metabolismo , Factores de Transcripción Forkhead/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Regiones Promotoras Genéticas , Transducción de Señal , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología
2.
Cancer Immunol Immunother ; 70(7): 1877-1891, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-33394094

RESUMEN

The initiation of new blood vessel formation (neo-angiogenesis) is one of the primary requirements for the establishment of tumor. As the tumor grows beyond a certain size, a hypoxic-condition arises in the inner core of tumor, triggering the release of chemokines, which attract T-regulatory (Treg) cells in the tumor-site. The presence of FOXP3, a lineage-specific transcription factor, expressing Treg cells in various types of tumor implements immunosuppressive and tumor-promoting strategies. One such strategy is the invitation of endothelial cells for neo-vascularization in the tumor site. Here we report that as the disease progresses, Treg cells from breast cancer patients are capable of secreting high-amount of VEGFA. The VEGFA promoter lacks Treg-specific transcription factor FOXP3 binding site. FOXP3 in association with locus-specific transcription factor STAT3 binds to VEGFA promoter to induce its transcription in Treg cells obtained from breast cancer patients. Treg cell-secreted VEGFA induces neo-angiogenesis from endothelial cells under in-vitro conditions. Targeting Tregs in mice with breast tumor reduces tumor growth as well as the level of neo-angiogenesis in the tumor tissue.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/patología , Regulación Neoplásica de la Expresión Génica , Neovascularización Patológica/patología , Linfocitos T Reguladores/inmunología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Apoptosis , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Estudios de Casos y Controles , Proliferación Celular , Células Endoteliales/metabolismo , Células Endoteliales/patología , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Neovascularización Patológica/genética , Neovascularización Patológica/inmunología , Neovascularización Patológica/metabolismo , Pronóstico , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Linfocitos T Reguladores/metabolismo , Células Tumorales Cultivadas , Factor A de Crecimiento Endotelial Vascular/genética , Ensayos Antitumor por Modelo de Xenoinjerto
3.
Sci Immunol ; 9(95): eadi7418, 2024 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-38758807

RESUMEN

Immune checkpoint blockade is a promising approach to activate antitumor immunity and improve the survival of patients with cancer. V-domain immunoglobulin suppressor of T cell activation (VISTA) is an immune checkpoint target; however, the downstream signaling mechanisms are elusive. Here, we identify leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) as a VISTA binding partner, which acts as an inhibitory receptor by engaging VISTA and suppressing T cell receptor signaling pathways. Mice with T cell-specific LRIG1 deletion developed superior antitumor responses because of expansion of tumor-specific cytotoxic T lymphocytes (CTLs) with increased effector function and survival. Sustained tumor control was associated with a reduction of quiescent CTLs (TCF1+ CD62Lhi PD-1low) and a reciprocal increase in progenitor and memory-like CTLs (TCF1+ PD-1+). In patients with melanoma, elevated LRIG1 expression on tumor-infiltrating CD8+ CTLs correlated with resistance to immunotherapies. These results delineate the role of LRIG1 as an inhibitory immune checkpoint receptor and propose a rationale for targeting the VISTA/LRIG1 axis for cancer immunotherapy.


Asunto(s)
Antígenos B7 , Linfocitos T CD8-positivos , Glicoproteínas de Membrana , Microambiente Tumoral , Animales , Humanos , Ratones , Antígenos B7/inmunología , Antígenos B7/genética , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Glicoproteínas de Membrana/inmunología , Glicoproteínas de Membrana/genética , Proteínas de la Membrana , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas del Tejido Nervioso , Microambiente Tumoral/inmunología
4.
Front Immunol ; 14: 1264327, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37928556

RESUMEN

The differentiation, survival, and effector function of tumor-specific CD8+ cytotoxic T cells lie at the center of antitumor immunity. Due to the lack of proper costimulation and the abundant immunosuppressive mechanisms, tumor-specific T cells show a lack of persistence and exhausted and dysfunctional phenotypes. Multiple coinhibitory receptors, such as PD-1, CTLA-4, VISTA, TIGIT, TIM-3, and LAG-3, contribute to dysfunctional CTLs and failed antitumor immunity. These coinhibitory receptors are collectively called immune checkpoint receptors (ICRs). Immune checkpoint inhibitors (ICIs) targeting these ICRs have become the cornerstone for cancer immunotherapy as they have established new clinical paradigms for an expanding range of previously untreatable cancers. Given the nonredundant yet convergent molecular pathways mediated by various ICRs, combinatorial immunotherapies are being tested to bring synergistic benefits to patients. In this review, we summarize the mechanisms of several emerging ICRs, including VISTA, TIGIT, TIM-3, and LAG-3, and the preclinical and clinical data supporting combinatorial strategies to improve existing ICI therapies.


Asunto(s)
Receptor 2 Celular del Virus de la Hepatitis A , Neoplasias , Humanos , Neoplasias/metabolismo , Inmunoterapia , Receptores Inmunológicos/metabolismo , Linfocitos T Citotóxicos
5.
Discov Oncol ; 14(1): 220, 2023 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-38038865

RESUMEN

Cancer stem cells (CSCs), being the primary contributors in tumor initiation, metastasis, and relapse, ought to have seminal roles in evasion of immune surveillance. Tumor-promoting CD4+CD25+FOXP3+ T-regulatory cells (Tregs) have been described to abolish host defense mechanisms by impeding the activities of other immune cells including effector T cells. However, whether CSCs can convert effector T cells to immune-suppressive Treg subset, and if yes, the mechanism underlying CSC-induced Treg generation, are limitedly studied. In this regard, we observed a positive correlation between breast CSC and Treg signature markers in both in-silico and immunohistochemical analyses. Mirroring the conditions during tumor initiation, low number of CSCs could successfully generate CD4+CD25+FOXP3+ Treg cells from infiltrating CD4+ T lymphocytes in a contact-independent manner. Suppressing the proliferation potential as well as IFNγ production capacity of effector T cells, these Treg cells might be inhibiting antitumor immunity, thereby hindering immune-elimination of CSCs during tumor initiation. Furthermore, unlike non-stem cancer cells (NSCCs), CSCs escaped doxorubicin-induced apoptosis, thus constituting major surviving population after three rounds of chemotherapy. These drug-survived CSCs were also able to generate CD4+CD25+FOXP3+ Treg cells. Our search for the underlying mechanism further unveiled the role of CSC-shed immune-suppressive cytokine TGFß, which was further increased by chemotherapy, in generating tumor Treg cells. In conclusion, during initiation as well as after chemotherapy, when NSCCs are not present in the tumor microenvironment, CSCs, albeit present in low numbers, generate immunosuppressive CD4+CD25+FOXP3+ Treg cells in a contact-independent manner by shedding high levels of immune-suppressive Treg-polarizing cytokine TGFß, thus escaping immune-elimination and initiating the tumor or causing tumor relapse.

6.
Cancer Immunol Res ; 11(3): 364-380, 2023 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-36574614

RESUMEN

B cells are an essential component of humoral immunity. Their primary function is to mount antigen-specific antibody responses to eliminate pathogens. Despite an increase in B-cell number, we found that serum-IgG levels were low in patients with breast cancer. To solve this conundrum, we used high-dimensional flow cytometry to analyze the heterogeneity of B-cell populations and identified a tumor-specific CD19+CD24hiCD38hi IL10-producing B regulatory (Breg)-cell subset. Although IL10 is a Breg-cell marker, being an intracellular protein, it is of limited value for Breg-cell isolation. Highly expressed Breg-cell surface proteins CD24 and CD38 also impede the isolation of viable Breg cells. These are hurdles that limit understanding of Breg-cell functions. Our transcriptomic analysis identified, CD39-negativity as an exclusive, sorting-friendly surface marker for tumor-associated Breg cells. We found that the identified CD19+CD39‒IL10+ B-cell population was suppressive in nature as it limited T helper-cell proliferation, type-1 cytokine production, and T effector-cell survival, and augmented CD4+FOXP3+ regulatory T-cell generation. These tumor-associated Breg cells were also found to restrict autologous T follicular helper-cell expansion and IL21 secretion, thereby inhibiting germinal transcript formation and activation-induced cytidine deaminase expression involved in H-chain class-switch recombination (CSR). This isotype-switching abnormality was shown to hinder B-cell differentiation into class-switched memory B cells and subsequent high-affinity antibody-producing plasma B cells, which collectively led to the dampening of IgG-mediated antibody responses in patients with cancer. As low IgG is associated with poor prognosis in patients with cancer, Breg-cell depletion could be a promising future therapy for boosting plasma B cell-mediated antibody responses.


Asunto(s)
Interleucina-10 , Neoplasias , Humanos , Formación de Anticuerpos , Antígenos CD19 , Linfocitos T CD4-Positivos , Inmunoglobulina G
7.
Front Pharmacol ; 12: 731492, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34795581

RESUMEN

The conventional carcinoma treatment generally encompasses the employment of radiotherapy, chemotherapy, surgery or use of cytotoxic drugs. However, recent advances in pharmacological research have divulged the importance of traditional treatments in cancer. The aim of the present review is to provide an overview of the importance of one such medicinal herb of Chinese and Indian origin: Andrographis paniculate on colorectal cancer with special emphasis on its principal bioactive component andrographolide (AGP) and its underlying mechanisms of action. AGP has long been known to possess medicinal properties. Studies led by numerous groups of researchers shed light on its molecular mechanism of action. AGP has been shown to act in a multi-faceted manner in context of colorectal cancer by targeting matrix metalloproteinase-9, Toll-like receptor or NFκB signaling pathways. In this review, we highlighted the recent studies that show that AGP can act as an effective immunomodulator by harnessing effective anti-tumor immune response. Recent studies strongly recommend further research on this compound and its analogues, especially under in-vivo condition to assess its actual potential as a prospective and efficient candidate against colorectal cancer. The current review deals with the roles of this phytomedicine in context of colorectal cancer and briefly describes its perspectives to emerge as an essential anti-cancer drug candidate. Finally, we also point out the drawbacks and difficulties in administration of AGP and indicate the use of nano-formulations of this phytomedicine for better therapeutic efficacy.

8.
Sci Rep ; 7(1): 1628, 2017 05 09.
Artículo en Inglés | MEDLINE | ID: mdl-28487507

RESUMEN

T-regulatory cells are an upsurge in the tumor microenvironment and induce immune-evasion. CD4+ Treg cells are well characterized whereas the role of CD8+ Tregs in cancer has recently started to crease attention. Here, we report an augmentation CD8+FOXP3+ Tregs in breast tumor microenvironment. FOXP3, the lineage-specific transcription factor, is a dominant regulator of Treg cell development and function. FOXP3 is induced preferentially by divergent signaling in CD4+ Treg cells. But how FOXP3 is induced and maintained in tumor-CD8+ Tregs is the Cinderella of the investigation. We observed that RUNX3, a CD8+ lineage-specific transcription factor, binds at the FOXP3-promoter to induce its transcription. In addition to promoter activation, involvement of cis-elements CNS1 and CNS2 in the transcriptional regulation of FOXP3 was also evident in these cells. SMAD3 binds to CNS1 region and acts as transcription inducer, whereas GATA3 plays a temporal role in the FOXP3 transcription by differential chromatin modification in CNS regions. In CNS1 region, GATA3 acts as a repressor for FOXP3 in naïve CD8+ T cells. Whereas in CD8+ Tregs, GATA3 binds directly at CNS2 region and persuaded the maintenance of FOXP3. Therefore, the intervention of these concerted transcriptional machinery may have a therapeutic potential in immunotherapy of cancer.


Asunto(s)
Linfocitos T CD8-positivos/metabolismo , ADN Intergénico/genética , Factores de Transcripción Forkhead/genética , Regulación de la Expresión Génica , Regiones Promotoras Genéticas , Linfocitos T Reguladores/metabolismo , Transcripción Genética , Adolescente , Adulto , Animales , Secuencia de Bases , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Secuencia Conservada/genética , Subunidad alfa 3 del Factor de Unión al Sitio Principal/metabolismo , Femenino , Factores de Transcripción Forkhead/metabolismo , Factor de Transcripción GATA3/metabolismo , Humanos , Terapia de Inmunosupresión , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Ratones Endogámicos BALB C , Persona de Mediana Edad , Modelos Genéticos , Proteína smad3/metabolismo , Microambiente Tumoral , Adulto Joven
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