Immunomodulatory roles of Tie-2+ MDSCs and concomitant chemoradiation in Non-Small Cell Lung Cancers ; Rôles immunomodulateurs des MDSC Tie-2+ et de la radiochimiothérapie dans les cancers bronchiques non à petites cellules

Monoclonal antibodies targeting immune checkpoints (ICPs) have revolutionized the management of cancers. However, these immunostimulatory therapies are effective in a small proportion of patients.One of the major obstacles to their effectiveness is a tumor microenvironment hostile to the effectors of antitumor immunity, especially T cells. A better understanding of anti-tumor immunity and mechanisms driving resistance to ICP blockade are required to sensitize patients to these promising therapies. Here, we studied a subpopulation of immunosuppressive myeloid cells (MDSC) which is likely to play a major role in this resistance. In the second part of this work, we analyzed the effect of concomitant chemoradiation (RTCT) on the tumor immune microenvironment and wondered how it could counteract with resistance to ICP blockade.First, we showed in a cohort of Non-Small Cell Lung Cancer patients (NSCLC) the expansion of monocytic MDSC populations (M-MDSC) overexpressing Tie-2, a tyrosine kinase receptor which binds the pro-angiogenic factor angiopoietin-2 (Ang-2). A positive correlation has been measured between percentages of Tie2+ M-MDSC and Ang-2 serum level. Furthermore, the presence of a strong Tie2+ M-MDSC/Ang-2 signature was associated with a decrease or loss of T cells responses against NY-ESO1, Telomerase and WT-1, whereas anti-viruses T cell responses were preserved. Indeed, we have demonstrated that Ang-2 increased Tie2+ M-MDSC suppressive activity. In addition, a high Ang-2/ Tie-2+ M-MDSC signature was associated with suppressive cytokines such as VEGF and TGF-β and the accumulation of circulating regulatory T cells. Our results could therefore explain the poor prognosis associated with a strong Ang-2/ Tie-2+ M-MDSC signature in our cohort. Thus, Tie-2 could be used as a phenotypic marker to study suppressive M-MDSC. So, our study open new prospects for the evaluation of Ang-2/ Tie-2+ M-MDSC as a mechanism involved in ICP blockade resistance in NSCLC.In the second part of this project, we used a ...