Comprehensive analysis of current approaches to inhibit regulatory T cells in cancer

CD4+CD25+Foxp3+ regulatory T cells (Treg) have emerged as a dominant T cell population inhibiting anti-tumor effector T cells. Initial strategies used for Treg-depletion (cyclophosphamide, anti-CD25 mAb…) also targeted activated T cells, as they share many phenotypic markers. Current, ameliorated approaches to inhibit Treg aim to either block their function or their migration to lymph nodes and the tumor microenvironment. Various drugs originally developed for other therapeutic indications (anti-angiogenic molecules, tyrosine kinase inhibitors,etc) have recently been discovered to inhibit Treg. These approaches are expected to be rapidly translated to clinical applications for therapeutic use in combination with immunomodulators

Mild dyslipidemia accelerates tumorigenesis through expansion of Ly6Chi monocytes and differentiation to pro-angiogenic myeloid cells

Cancer and cardiovascular disease (CVD) share common risk factors such as dyslipidemia, obesity and inflammation. However, the role of pro-atherogenic environment and its associated low-grade inflammation in tumor progression remains underexplored. Here we show that feeding C57BL/6J mice with a non-obesogenic high fat high cholesterol diet (HFHCD) for two weeks to induce mild dyslipidemia, increases the pool of circulating Ly6Chi monocytes available for initial melanoma development, in an IL-1β-dependent manner. Descendants of circulating myeloid cells, which accumulate in the tumor microenvironment of mice under HFHCD, heighten pro-angiogenic and immunosuppressive activities locally. Limiting myeloid cell accumulation or targeting VEGF-A production by myeloid cells decrease HFHCD-induced tumor growth acceleration. Reverting the HFHCD to a chow diet at the time of tumor implantation protects against tumor growth. Together, these data shed light on cross-disease communication between cardiovascular pathologies and cancer

Vaccination-based immunotherapy to target profibrotic cells in liver and lung

Fibrosis is the final path of nearly every form of chronic disease, regardless of the pathogenesis. Upon chronic injury, activated, fibrogenic fibroblasts deposit excess extracellular matrix, and severe tissue fibrosis can occur in virtually any organ. However, antifibrotic therapies that target fibrogenic cells, while sparing homeostatic fibroblasts in healthy tissues, are limited. We tested whether specific immunization against endogenous proteins, strongly expressed in fibrogenic cells but highly restricted in quiescent fibroblasts, can elicit an antigen-specific cytotoxic T cell response to ameliorate organ fibrosis. In silico epitope prediction revealed that activation of the genes Adam12 and Gli1 in profibrotic cells and the resulting “self-peptides” can be exploited for T cell vaccines to ablate fibrogenic cells. We demonstrate the efficacy of a vaccination approach to mount CD8+ T cell responses that reduce fibroblasts and fibrosis in the liver and lungs in mice. These results provide proof of principle for vaccination-based immunotherapies to treat fibrosis

High Therapeutic Efficacy of a New Survivin LSP-Cancer Vaccine Containing CD4+ and CD8+ T-Cell Epitopes

The efficacy of an antitumoral vaccine relies both on the choice of the antigen targeted and on its design. The tumor antigen survivin is an attractive target to develop therapeutic cancer vaccines because of its restricted over-expression and vital functions in most human tumors. Accordingly, several clinical trials targeting survivin in various cancer indications have been conducted. Most of them relied on short peptide-based vaccines and showed promising, but limited clinical results. In this study, we investigated the immunogenicity and therapeutic efficacy of a new long synthetic peptide (LSP)-based cancer vaccine targeting the tumor antigen survivin (SVX). This SVX vaccine is composed of three long synthetic peptides containing several CD4+ and CD8+ T-cell epitopes, which bind to various HLA class II and class I molecules. Studies in healthy individuals showed CD4+ and CD8+ T-cell immunogenicity of SVX peptides in human, irrespective of the individual's HLA types. Importantly, high frequencies of spontaneous T-cell precursors specific to SVX peptides were also detected in the blood of various cancer patients, demonstrating the absence of tolerance against these peptides. We then demonstrated SVX vaccine's high therapeutic efficacy against four different established murine tumor models, associated with its capacity to generate both specific cytotoxic CD8+ and multifunctional Th1 CD4+ T-cell responses. When tumors were eradicated, generated memory T-cell responses protected against rechallenge allowing long-term protection against relapses. Treatment with SVX vaccine was also found to reshape the tumor microenvironment by increasing the tumor infiltration of both CD4+ and CD8+ T cells but not Treg cells therefore tipping the balance toward a highly efficient immune response. These results highlight that this LSP-based SVX vaccine appears as a promising cancer vaccine and warrants its further clinical development

Impact de l interaction CD40/CD40L sur les différents intervenants de la réponse immunitaire T CD8

PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF

Les mécanismes de différenciation des lymphocytes T CD8 en cellules mémoires

Dans cette étude, nous avons montré la multiplicité de l'effet helper des cellules TCD4 sur les différents aspects des réponses CD8: prolifération, survie, fonctions effectrices et différenciation en cellule mémoire. Ces effets helper impliquent la signalisation CD40 ainsi que d'autres signaux. L'expression de CD40 par les CFA et les cellules TCD8 joue un rôle direct et complémentaire: l'expression de CD40 par les CFA est importante pour l'expansion des cellules TCD8; l'expression de CD40 par les cellules TCD8 est cruciale pour leur différenciation en cellule mémoire. En réponse secondaire, la déficience en CD40 des cellules TCD8 altère leur expansion, leur capacité de contrôle de la charge antigénique, leurs fonctions effectrices, leur sensibilité aux cytokines d'activation/survie et augmente leur sensibilité aux cytokines inhibitrices. L'expression de CD40 par les cellules TCD8 est ainsi strictement impliquée dans l'établissement du programme de différenciation en cellule mémoire.In this study, we showed the multiplicity of CD4 T cell help on the different aspects of CDS responses: proliferation, survival, effectors functions and memory cell differentiation. This help involves CD40 signalization and others signals. CD40 expression on APC and on CD8 T cells play a direct and complementary role: CD40 expression on APC is important for CD8 T cell expansion; CD40 expression on CD8 T cells is crucial for their differentiation into memory cell. During secondary response, CD40 deficiency on CD8 T cells alters their expansion, their capacity of control of antigen load, their effectors functions, their sensibility toward activating/surviving cytokines and increases their sensibility toward inhibitory cytokines. CD40 expression on CD8 T cells is also strictly involved into the establishment of the memory cell differentiation program.PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF

Therapeutic Cancer Vaccine and Combinations With Antiangiogenic Therapies and Immune Checkpoint Blockade

International audienceConsidering the high importance of immune surveillance and immune escape in the evolution of cancer, the development of immunotherapeutic strategies has become a major field of research in recent decades. The considerable therapeutic breakthrough observed when targeting inhibitory immune checkpoint molecules has highlighted the need to find approaches enabling the induction and proper activation of an immune response against cancer. In this context, therapeutic vaccination, which can induce a specific immune response against tumor antigens, is an important approach to consider. However, this strategy has its advantages and limits. Considering its low clinical efficacy, approaches combining therapeutic cancer vaccine strategies with other immunotherapies or targeted therapies have been emphasized. This review will list different cancer vaccines, with an emphasis on their targets. We highlight the results and limits of vaccine strategies and then describe strategies that combine therapeutic vaccines and antiangiogenic therapies or immune checkpoint blockade. Antiangiogenic therapies and immune checkpoint blockade are of proven clinical efficacy for some indications, but are limited by toxicity and the development of resistance. Their combination with therapeutic vaccines could be a way to improve therapeutic outcome by specifically stimulating the immune system and considering a global approach to tumor microenvironment remodeling