The Forkhead Box Protein 3 is highly expressed not only in regulatory T cells, but also in tumor cells, acting as a transcriptional repressor of breast oncogenes including HER2. We investigated the ...prognostic significance of Foxp3 expression in cancer cells in a large cohort of patients with HER2-overexpressing breast carcinoma treated with neoadjuvant chemotherapy. Foxp3-positive tumor cells were detected by immunohistochemistry in 103 patients with primary invasive HER2-overexpressing breast carcinoma, and treated with neoadjuvant chemotherapy, with or without trastuzumab. Kaplan-Meier analysis and Cox regression model were used to assess relapse-free and overall survival, respectively, and according to the presence or the absence of Foxp3 expression in tumor cells. Breast cancer cells were Foxp3+ in 57% of tumors. Foxp3 expression in breast cancer cells was associated with better relapse-free (P = 0.005) and overall survival (P = 0.03). By multivariate analysis, the presence of Foxp3+ tumor cells produced an independent prognostic factor for both better relapse-free (P = 0.006) and overall survival (P = 0.03). These findings indicate that the presence of Foxp3+ tumor cells represents a new independent prognostic factor of improved outcome in HER2-overexpressing breast carcinoma, which could help identify high-risk patients for additional therapies after neoadjuvant chemotherapy.
Adaptive T cell immune response is essential for tumor growth control. The efficacy of immune checkpoint inhibitors is regulated by intratumoral immune response. The tumor microenvironment has a ...major role in adaptive immune response tuning. Tumor cells generate a particular metabolic environment in comparison to other tissues. Tumors are characterized by glycolysis, hypoxia, acidosis, amino acid depletion and fatty acid metabolism modification. Such metabolic changes promote tumor growth, impair immune response and lead to resistance to therapies. This review will detail how these modifications strongly affect CD8 and CD4 T cell functions and impact immunotherapy efficacy.
(1) Background: Immunosuppression is a key barrier to effective anti-cancer therapies, particularly in triple-negative breast cancer (TNBC), an aggressive and difficult to treat form of breast ...cancer. We investigated here whether the combination of doxorubicin, a standard chemotherapy in TNBC with glyceryltrinitrate (GTN), a nitric oxide (NO) donor, could overcome chemotherapy resistance and highlight the mechanisms involved in a mouse model of TNBC. (2) Methods: Balb/C-bearing subcutaneous 4T1 (TNBC) tumors were treated with doxorubicin (8 mg/Kg) and GTN (5 mg/kg) and monitored for tumor growth and tumor-infiltrating immune cells. The effect of treatments on MDSCs reprogramming was investigated ex vivo and in vitro. (3) Results: GTN improved the anti-tumor efficacy of doxorubicin in TNBC tumors. This combination increases the intra-tumor recruitment and activation of CD8
lymphocytes and dampens the immunosuppressive function of PMN-MDSCs PD-L1
. Mechanistically, in PMN-MDSC, the doxorubicin/GTN combination reduced STAT5 phosphorylation, while GTN +/- doxorubicin induced a ROS-dependent cleavage of STAT5 associated with a decrease in FATP2. (4) Conclusion: We have identified a new combination enhancing the immune-mediated anticancer therapy in a TNBC mouse model through the reprograming of PMN-MDSCs towards a less immunosuppressive phenotype. These findings prompt the testing of GTN combined with chemotherapies as an adjuvant in TNBC patients experiencing treatment failure.
Expression of the Autoimmune regulator (AIRE) outside of the thymus has long been suggested in both humans and mice, but the cellular source in humans has remained undefined. Here we identify AIRE ...expression in human tonsils and extensively analyzed these "extra-thymic AIRE expressing cells" (eTACs) using combinations of flow cytometry, CyTOF and single cell RNA-sequencing. We identified AIRE+ cells as dendritic cells (DCs) with a mature and migratory phenotype including high levels of antigen presenting molecules and costimulatory molecules, and specific expression of CD127, CCR7, and PDL1. These cells also possessed the ability to stimulate and re-stimulate T cells and displayed reduced responses to toll-like receptor (TLR) agonists compared to conventional DCs. While expression of
was enriched within CCR7+CD127+ DCs, single-cell RNA sequencing revealed expression of
to be transient, rather than stable, and associated with the differentiation to a mature phenotype. The role of AIRE in central tolerance induction within the thymus is well-established, however our study shows that
expression within the periphery is not associated with an enriched expression of tissue-restricted antigens (TRAs). This unexpected finding, suggestive of wider functions of AIRE, may provide an explanation for the non-autoimmune symptoms of APECED patients who lack functional AIRE.
MDSC (myeloid derived suppressor cells) are immature cells from myeloid origin that accumulate in spleen and tumor bed during tumor growth and that can suppress anti-tumor immunity by various ways. ...Two chemotherapeutic agents, 5-fluorouracil and gemcitabin, that are commonly used in the treatment of colon cancer and pancreatic cancer, can selectively kill MDSC. Beneficial effects of 5-Fluorouracil and gemcitabin are however temporary. After treatment with those chemotherapies, an activation of the NLRP3 inflammasome is observed in MDSC, due to an interaction between cathepsin B and NLRP3, which leads to the production of IL-1β thus increasing pro-tumor immune responses. IL-1β enhances the production of IL-17 by CD4 T cells which in turn favors angiogenesis and tumor growth.
Activation of the transcription factor PPARγ by the n-3 fatty acid docosahexaenoic acid (DHA) is implicated in controlling proinflammatory cytokine secretion, but the intracellular signaling pathways ...engaged by PPARγ are incompletely characterized. Here, we identify the adapter-encoding gene SOCS3 as a critical transcriptional target of PPARγ. SOCS3 promoter binding and gene transactivation by PPARγ was associated with a repression in differentiation of proinflammatory T-helper (TH)17 cells. Accordingly, TH17 cells induced in vitro displayed increased SOCS3 expression and diminished capacity to produce interleukin (IL)-17 following activation of PPARγ by DHA. Furthermore, naïve CD4 T cells derived from mice fed a DHA-enriched diet displayed less capability to differentiate into TH17 cells. In two different mouse models of cancer, DHA prevented tumor outgrowth and angiogenesis in an IL-17-dependent manner. Altogether, our results uncover a novel molecular pathway by which PPARγ-induced SOCS3 expression prevents IL-17-mediated cancer growth.
Microenvironnement tumoral Bruchard, Mélanie; Ghiringhelli, François
M.S. Médecine sciences,
04/2014, Letnik:
30, Številka:
4
Journal Article
Recenzirano
Odprti dostop
L’immunosuppression est un des mécanismes développés par les cellules cancéreuses pour échapper au système immunitaire. Elle implique l’expansion de divers types cellulaires et la production de ...cytokines variées. Nous présentons dans cet article la dualité des effets de trois populations cellulaires suppressives induites lorsque se développe un cancer - les lymphocytes T régulateurs, les lymphocytes Th17 et les MDSC (myeloid-derived suppressor cells) - ainsi que les effets pléiotropes de plusieurs cytokines sécrétées dans le cas de cancer.
Immunosuppression is a mechanism developed by cancer cells to help them escape the immune system. Immunosuppression involves expansion of various cell types and production of a variety of cytokines. In this review, we explore the duality of three cancer induced cell populations, regulatory T lymphocytes, Th17 lymphocytes and MDSC, and also the pleiotropic effects of several cytokines induced during cancer development.
Immunosuppression is a mechanism developed by cancer cells to help them escape the immune system. Immunosuppression involves expansion of various cell types and production of a variety of cytokines. ...In this review, we explore the duality of three cancer induced cell populations, regulatory T lymphocytes, Th17 lymphocytes and MDSC, and also the pleiotropic effects of several cytokines induced during cancer development.
Immunosuppression is a mechanism developed by cancer cells to help them escape the immune system. Immunosuppression involves expansion of various cell types and production of a variety of cytokines. ...In this review, we explore the duality of three cancer induced cell populations, regulatory T lymphocytes, Th17 lymphocytes and MDSC, and also the pleiotropic effects of several cytokines induced during cancer development.
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