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

Study Overview
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Brief Summary
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Immunotherapy have revolutionized the field of oncology, but response rates are low and all patients relapse, due to cellular and soluble immunosuppressive mechanisms. These immunosuppressive mechanisms will be better characterized and their involvement in therapeutic responses in non-small cell lung cancers (NSCLC). Indeed, large transcriptomic analysis of different subsets of immunosuppressive cells will performed, correlating them to clinical outcome in a cohort of stage III disease, treated by radiochemotherapy and immunotherapy as maintenance, and stage IV treated by immunotherapy as first-line treatment. Furthermore, we will analyse cellular mechanisms by in vitro studies, assessing the effect of immunosuppressive cells, provided by fresh tumor samples, on phenotype and functions of lung cancer cell lines. The aim of this study is to better characterize immunosuppressive landscape of NSCLC and mechanisms involved in their protumor functions.

Detailed Description
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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).

Official Title
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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

Conditions
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Lung Neoplasm, Cancer Associated Fibroblast, Myeloid-Derived Suppressive Cells Immunosuppression

Intervention / Treatment
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* Procedure: Tumor samples


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Prospective part of the study<br> | Procedure: Tumor samples<br>* Tumor samples will be collected by the pathologist at the reception of the tumor removed during surgery<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Descriptive analysis of immune infiltration and phenotypic and functional characteristics of the different cell subgroups isolated from fresh tumors | Exploratory analysis of the immune infiltration (phenotype and function of immunosuppressive and antitumor immune cells) and of the cancer-associated fibroblasts through a transcriptomic analysis of fresh resected lung carcinoma, comparing patients with lymph node involvement or not. Bioinformatics analysis of gene panels | At the time of surgery only, when fresh tumor is resected | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation between the infiltration of CAF and immunosuppressive immune cells and with clinicopathological parameters and patient prognosis (relapse free-survival, overall survival) in stage III NSCLC exposed to immunotherapy | Analyze CAF and immunosuppressive immune infiltration in a cohort of unresectable stage III lung carcinoma treated with radiochemotherapy followed by immunotherapy, assessing correlation between immunosuppressive subpopulations and clinical parameters and patient outcome. We will use a multiplexing immunofluorescence assay | Between September 2018 and December 2021, receiving concomitant radiochemotherapy followed by durvalumab (maintenance) | 
| Comparative analysis of the modifications of phenotype and functions of MDSC and T lymphocytes when exposed to CAF extracted from patient tumor tissue | Functional in vitro studies of the effect of CAF on phenotype and function of T lymphocytes and of MDSC being extracted from resected NSCLC prospectively collected | At the time of surgery only, when fresh tumor is resected | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lung cancer, Immunosuppression, Immunotherapy, Immuno-oncology, Antitumor immune escape