Professor Salem Chouaib

Country: France

Institution: Integrative Tumor Immunology laboratory, Gustave Roussy

Research Areas: Cancer immunology

Lab Website: www.gustaveroussy.fr/en

Despite the significant progress during the last decade in antitumor immunotherapy and cancer vaccine approaches, there is still a need for more effective treatments to maximize cancer patient survival rates. In this regard, novel combined strategies for tumor target selection, vaccine design and immunostimulatory intervention are being developed in the context of tumor microenvironment (TME) complexity and heterogogeneity. The role of TME during the initiation and progression of carcinogenesis is presently considered to be of critical importance, both for better understanding of fundamental cancer biology and for exploiting this source of relatively new knowledge to improve molecular diagnostics and therapeutics. Our team has over last years accumulated evidence indicating that hypoxia in the tumor microenvironment plays a central role in the evolution of immune escape mechanisms by tumor cells through its impact on immune plasticity and tumor heterogeneity. Therefore, targeting tumor hypoxia and its associated pathways might be a new strategy to better control tumor invasiveness, the emergence of resistant tumor variants and ensure more effective cancer therapies. The specific goal of the current research program is therefore to increase our knowledge on the regulation of antitumor immune response in the context of micro-environmental complexity and reprogramming in order to better target tumor stroma and design innovative integrative and instructive immunotherapy approaches.

We are focusing on the following:

1) Further elucidating the role of hypoxic stress in immunosuppression and tumor resistance to immune surveillance, with a focus on the effect of hypoxia on cytotoxic T lymphocytes (CTL) and the induction of immune tolerance. How hypoxic stress interferes with DNA repair and may induce tumor immunogenicity will also be investigated, and combined treatments based on targeting hypoxia-associated pathways and potentiating T-cell responses will be developed in preclinical models; 2) Evaluating the effect of P53 gene mutations and pharmacological p53 reactivation on tumor cell sensitivity to effector cell-mediated lysis. Whether reactivation of p53 sensitizes tumor cells to effector cell killing, decreases PD-L1 expression and delays tumor progression and invasion will also be assessed; 3) 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; 4) 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 use on immune infiltrates and signature to explore the clinical question of sequence will also be assessed. Through its various aspects, the aim of our program will be to better understand how the TME can influence the behavior and functions of effector T cells and affect response to ICB. Our goal is to improve current cancer immunotherapies and contribute to the development of more effective combination treatments. To do so, we have access to all GR’s platforms and have established solid interaction with clinicians. Our unit belongs to several research networks, is attractive for post-doc and young scientists, and has established numerous national and international collaborations.