Objective of the thesis: to participate in the research theme summarized below and to take charge of part of it. This project is financed by a PRT-K grant and is a collaborative work Saclay/Paris/Grenoble
Knowledge of immunology and basic immunology techniques. Valued multidisciplinarity, in particular in relation to bioinformatics/biostatistics.
Summary of the research theme 2023-2025
T cells specific for tumor antigens play a central role in anti-tumor immunity and immunotherapy. However, recent data show that they constitute only a fraction of tumor-infiltrating T cells (TILs), and that many TILs (called 'bystanders') recognize non-tumor antigens.
Immunotherapeutic strategies using these bystander T cells are at the preclinical stage. Our work on the HLA-G/ILT2 inhibitory checkpoint in patients with urological cancers shows that alongside PD1+ TILs known to be antitumor and specific for tumor antigens, ILT2+ TILs constitute a significant reservoir of highly cytotoxic lymphocytes, sensitive to inhibition by HLA-G but not by PDL1, and therefore insensitive to anti-PD1/-PDL1 immunotherapies. These ILT2+ TILs are anti-viral, and their activation may be of the innate type, independent of the TCR. ILT2+ T lymphocytes are therefore potentially anti-tumor bystander TILs. This situation is specifically human and cannot be observed in animal models in which the HLA-G/ILT2 checkpoint does not exist. The transition from preclinical to clinical therefore requires studies in humans.
Our goal is to demonstrate in urological cancers that
(i) when designing new immunotherapies based on bystander TILs, HLA-G, their main inhibitory checkpoint must absolutely be taken into account,
(ii) a therapeutic strategy can take advantage of the large population of intratumoral ILT2+ bystanders and their large reservoir of peripheral precursors, to redirect their functions specifically towards tumor cells while blocking their main inhibitory checkpoint HLA-G.
To achieve this objective, we brought together scientists from the CEA in onco-immunology (Paris) and bioinformatics (Grenoble), and oncologists, urologists and pathologists from Saint-Louis Hospital (Paris)