Role of Cancer-associated Fibroblast, MDSCs and Immune Cell Interplays in the Resistance of Non-small Cell Lung Cancer to Anti-PD1/PD-L1 Therapies

In recent years, immune-based therapies have revolutionized the field of oncology by significantly improving survival of cancer patients. Despite sustained responses, only 20% to 40% of cancer patients respond. It has become clear that the immunosuppressive environment induced by tumor through cellular and/or soluble pathways critically contribute to hinder efficient antitumor immunity. The inhibition of these immunosuppressive networks thus represents an essential prerequisite for the improvement of responses to anticancer immunotherapies. Several immune and non -immune cell populations have been identified as key actors of tumor-induced immunosuppression, among which are myeloid-derived suppressor cells (MDSC), and cancer associated fibroblasts (CAF). However, in non-small cell lung cancers (NSCLC), the phenotypic characteristics and the prognostic role of these cells, the mechanisms underlying their immunosuppressive functions, and their role in dampening the efficacy of immunotherapies in clinical practice are less characterized. The aim of this project is to better characterize these different immunosuppressive subpopulations, and to study their role promoting NSCLC development and resistance to immunotherapies.

First the tumor CAF and immunosuppressive microenvironment using single cell RNA sequencing will be characterized (objective 1a). After identification of phenotypic markers, the immunosuppressive landscape of stage III NSCLC on a lung cancer cohort treated at Bordeaux University Hospital will be analysed, and data on CAF, MDSC and immune infiltration will be correlated with tumor characteristics and cancer outcome (objective 1b). Finally, the pro-tumor functions of CAF isolated from lung cancer patients will be assessed in vitro (objective 2).

Inclusion criteria

• consecutive patients
• lung carcinoma surgically treated by surgery only (objectives 1a and 2), or stage III lung carcinoma treated by concomitant radiochemotherapy followed by durvalumab (maintenance) treated between September 2018 and december 2021 (objective 1b)

Exclusion criteria

• patient receiving chemotherapy, radiotherapy or immunotherapy in the neoadjuvant setting (all objectives)
• patient with previous cancer