Cancer Immunology and Immunotherapies.

The demonstration that immune-mediated mechanisms can lead to the specific elimination of cancer cells have brought immune-based interventions to the forefront of cancer therapeutics in modern oncology. However, it has also become clear that developing tumors can escape immune destruction by many mechanisms resulting in the subversion of immunoregulatory processes and leading to the inactivation of anti-tumor immunity. Correlatively, compelling evidence has indicated that inhibition of these cancer-induced immunosuppressive networks is an important prerequisite to uncover the full potential of immunotherapeutic approaches.

Our group conducts a basic and translational research program in cancer immunology and immunotherapy aimed at deciphering the mechanisms of tumor-induced immunosuppression and investigates approaches to override their negative impact on anti-cancer effector cells. A concomitant and complementary area of investigation centers on the propensity of several subsets of T lymphocytes to undergo reprogramming (the ability to trans-differentiate) into pro- or anti-cancer subsets under the influence of the underlying tumor environment. Immunotherapeutic-based strategies are also being explored.

We are specifically focusing on developing the following main axes:

As key controllers of innate and adaptive immune responses, CD4+ T helper (Th) lymphocytes play an essential role in cancer immunosurveillance. However, evidence has emerged that some subsets of Th cells, such as Th17 and Th9, can exhibit both pro- and anti-tumoral effects. This dichotomy has been attributed to the high plasticity of these cells capable of trans-differentiating into either pro-inflammatory effector or immunosuppressive populations (such as regulatory T lymphocytes, Treg) depending on the environment. In this context, the role of Th17 and Th9 in hosts with established malignancies and their possible therapeutic and prognostic value remain incompletely understood. The fact that Th17, Th9, Treg and their hybrid relatives share common differentiation pathways and cytokine requirements likely explains the plasticity of these different subsets and therefore their versatile function in cancer depending on the cytokine content, with TGFb as a likely master regulator among other factors. These questions are currently under investigation in our laboratory. Concomitantly, we are examining the role of T follicular helper (Tfh) in malignancies, specifically in chronic lymphocytic leukemia.

Although traditionally recognized as important anti-tumor cells playing an essential role in cancer immunosurveillance, gd T lymphocytes have recently been documented for their tumor-promoting activities. By analogy to their ab counterparts, it appears that, under specific conditions, gd T cells can also differentiate into distinct subsets endowed with either pro- or anti-tumoral functions. We are developing projects to characterize gd T cell subsets with pro- or anti-tumor activity, explore the influence of the tumor environment on the plasticity of these cells and evaluate the possibility to reprogram tumor-suppressing gd T lymphocytes into stable anti-tumor effectors.

The expansion of immunosuppressive cells represents a cardinal strategy deployed by cancers to avoid immune-mediated elimination. Besides Treg, cells of myeloid origin such as tumor-infiltrating tolerogenic dendritic cells (TiDC), type 2 macrophages (TAM) and myeloid-derived suppressor cells (MDSC) have drawn intense scrutiny for their tumor-promoting role. The modality of induction, the immuno-inhibitory function, the regulation, the pro-angiogenic/pro-metastatic activity and the therapeutic targeting of these cells are being explored. Because cancer-driven myeloid cell populations produce a variety of cytokines and chemokines which can potentially affect the differentiation, recruitment, proliferation and function of Treg, Th17, Th9, Tfh and gd T cells, deciphering the cross-talks between TiDC, TAM, MDSC and these lymphocyte populations is an essential question that we are currently pursuing.

“Cour des moines”, by Laura Rosenbaum

TEAM

T cell plasticity, immunosuppression

Head: Nicolas LARMONIER

Tumor DNA sensing

Head: Vanja SISIRAK (Idex chair)

PUBLICATIONS

Selected Publications

Complete list of publications

COLLABORATIONS

Collaborations with CNRS teams

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Université de Bordeaux

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Université de Bourgogne

Pr. Bernard Bonotte

University of Arizona

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FUNDING