The landscape and functions of innate immune cells in the tumor microenvironment and their role in immunotherapies

The innate immune contexture critically contributes to the tumor microenvironment, significantly impacts tumor development and dictates the outcome of therapies (immune-based, chemo-, or radiotherapies). A better comprehension of the role of these cells not only in immunological processes (tumor immune escape and immunosuppression) but also in the mechanisms of tumor invasion, metastasis and stemness is therefore essential.

1. Inflammasomes in CRC, Lung cancer, bladder cancer and glioblastoma multiforme (GBM). We and others have previously implicated the inflammasomes in suppressing tumorigenesis and in anti-tumor immunity. In this project, we wish to explore the mechanistic basis of these observations, i.e. interrogate the cell autonomous versus cell extrinsic roles of the inflammasome in tumor suppression and immune surveillance. Further, we wish to interrogate the role of the inflammasome in boosting the efficacy of immunotherapies. In the context of GBM, where >90% of immune cells in the tumor microenvironment are myeloid cells, the impact of inflammasome signaling on the phenotype and function of these cells and their role in promoting tumor growth is of major interest, especially taken the poor prognosis of this cancer. We are analyzing these questions in mouse models and through the analysis of patients surgical resections or biopsies.

2. Study myeloid-derived suppressor cells (MDSCs) in breast cancers and investigate the crosstalk between myeloid cells and Cancer Stem cells and Circulating tumor cells. a) We are characterizing in-depth the myeloid landscape to apprehend its complex heterogeneity as it relates to disease development, patient clinicopathological parameters and response to therapies in human breast cancers. b) In addition, we are deciphering the “non-immunologic” pro-tumoral properties of MDSCs. We are determining the role of different subpopulations of myeloid cells in tumor invasion, metastasis, and in the preparation of the pre-metastatic niche in murine cancer models. c) Along these lines, we are examining how myeloid cells impact cancer stemness in collaboration with experts in the field in Bordeaux (C. Varon).

3. Innate immune landscape in HCC etiologies and response to immunotherapies. Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. HCC prognosis is rather poor as the patients mOS is less than 2 years despite standard of care. The recent approval of immune checkpoint inhibitors (ICI) as a first or second treatment option in HCC has reinvigorated the study of liver-specific immunity. IIn this project, we wish to characterize the innate immunity landscape of HCC using single cell approaches, with respect to HCC etiologies (HCV/HBV infection, alcohol, metabolic syndrome) and the presence or absence of cirrhosis, and in relation to different HCC histological and molecular subtypes. We further wish to identify innate biomarkers of HCC patients’ response to ICI and identify potential innate immunotherapies that could be used as a monotherapy or in combination with ICI.

4. Immune landscape in bladder cancer post BCG-based immunotherapy. The immune contexture of non-muscle-invasive bladder cancer at different stages, with or without prior BCG or BCG plus Mitomycin c therapy are being characterized and correlated with clinical data.

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