UMR 1186 - Integrative tumor immunology and immunotherapy
Our laboratory highlighted several constitutive elements of the tumor environment (TME) involved in the regulation of antitumor T-cell response, in particular:
- the influence of TGF-β on the expression and signaling of CD103 in CD8+ resident memory T cells (TRM), and the role of this integrin to sustain specific cytotoxicity and to promote T-cell recruitment within epithelial tumor regions,
- the role of hypoxia, epithelial-mesenchymal transition (EMT) and p53 in controlling tumor cell susceptibility to T-cell-mediated killing, and
- the effect of Von Hippel-Lindau (VHL) gene mutations in promoting PD-L1 expression on cancer cells and escape from anti-PD-1 therapies. Our objective is to make new advances in the field of tumor resistance to T-cell-mediated cytotoxicity and immune checkpoint blockade (ICB) immunotherapy.
Theme 1 aims at:
- characterizing CD4+ TRM cells in human non-small cell lung cancer (NSCLC) and determining their role in regulating antitumor T-cell immunity and response to ICB using human and mouse tumor models;
- developing an air-liquid interface (ALI) culture system to study the cross-talks between lung cancer cells and immune cells, in particular cytotoxic T lymphocytes (CTL), and their consequences on both cell types;
- defining a composite immune signature predictive of clinical response to anti-PD-1 by assessing the involvement of TRM, antigen-presenting machinery (APM) in tumors and T-cell neoepitopes;
- studying the role of neuropilin (Nrp)-1 in regulating CD4+ effector T-cell functions and antitumor immune response, and 5) providing a proof of concept of a combination immunotherapy based on the preprocalcitonin (ppCT) peptide vaccine and anti-PD-1 in preclinical humanized mouse models. This last research axis has led to the foundation of a startup, ElyssaMed.
The objectives of Theme 2 are:
- further elucidating the role of hypoxic stress in immunosuppression and tumor resistance to immune surveillance, with a focus on the effects of hypoxia on CTL and the induction of immune tolerance. How hypoxic stress interferes with DNA repair and may induce tumor immunogenicity will be investigated. Combined treatments based on targeting hypoxia-associated pathways and potentiating T-cell responses will also be developed in preclinical models;
- evaluating the effect of P53 gene mutations and pharmacological p53 reactivation on tumor cell sensitivity to effector T-cell-mediated lysis. Whether reactivation of p53 sensitizes cancer cells to effector cell killing, decreases PD-L1 expression and delays tumor progression and invasion are questions that will also be asked;
- investigating the influence of EMT on the emergence of resistant tumor cell clones and the structure of the cytotoxic immune synapse between CTL and tumor cells in epithelial or mesenchymal-like states. Whether EMT transcription factor pathways promote tumor resistance to CTL will be determined by using a long-term 3D culture system to monitor the proliferation, differentiation and resistance of cancer cells to immune cells;
- determining the relationship between VHL mutations and tumor resistance to anti-PD-1. The impact of vascular endothelial growth factor (VEGF)-targeting agents prior to ICB on immune infiltrates and signature to explore the clinical question of sequence will also be explored.
Through its various aspects, the aim of our program is to better understand how the TME influences the behavior and functions of effector T cells, in particular TRM, and impacts response to immunotherapies. Our goal is to improve current cancer treatments and contribute to the development of more effective combination therapies. To do so, we have established solid interaction with clinicians from Gustave Roussy and have access to all Gustave Roussy’s platforms. Our unit belongs to several research networks, is attractive for young scientists and has established numerous national and international collaborations.