169P - High-dimensional analysis of tumor infiltrating immune cells reveals major differences in the tumor immune microenvironments of pleural mesothelioma and lung cancer

Background

Pleural mesothelioma (PM) and non-small cell lung cancer (NSCLC) are aggressive thoracic malignancies with different cells of origin, pathogenesis and genetic features. Despite both tumors are treated with chemotherapy and immunotherapy, patients with PM and NSCLC exhibit varying responses. The aim of this study is to characterize the differences in tumor infiltrating immune cell populations in PM and NSCLC using high-dimensional flow cytometry analysis.

Methods

Fresh-frozen tumors derived from 42 PM and 30 NSCLC patients with available clinical data were analyzed. Single-cell suspensions were stained with a panel of 33 markers and samples were acquired using a Spectral Analyzer. An R-based pipeline for the in-depth characterization of the immune cells subsets was developed. Machine learning methods were used for unsupervised phenotypes discovery and differential abundant analysis was carried out to identify differences between samples. Correlation analysis with available clinical data was performed.

Results

By using high-dimensional single-cell analysis, 18 tissue-resident and invading immune cells subsets within the tumor immune microenvironment (TIME) of PM and NSCLC samples were identified. The comparison between the two tumor entities reveled significant differences in the tumor landscape, with increased infiltration of CD4+ and CD8+ T cell subsets in NSCLC compared to PM. While NSCLC tumors share similar tumor infiltrating immune cell subsets, PM tumors cluster in three distinct subgroups. Specifically, the subgroup with decreased infiltration of B cells and increased presence of tumor-associated macrophages is characterized by a significant worse overall survival (6 vs 18 vs 27 months, p=0.00012).

Conclusions

Our findings demonstrate significant differences in the composition of the TIME between PM and NSCLC, especially in T cell abundance. These disparities offer insights into the varying responses to immunotherapy. Moreover, we highlight the pivotal role of the TIME in predicting PM patient outcomes. These findings may be crucial to optimize immunotherapy for these malignancies, potentially leading to improve patients' outcomes.

Legal entity responsible for the study

The authors.

Funding

Stiftung für Angewandte Krebsforschung (SAKF).

Disclosure

I. Opitz: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca; Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, BMS; Financial Interests, Personal, Other, Proctorship: Intuitive; Financial Interests, Institutional, Research Grant: Medtronic, Roche. A. Curioni-Fontecedro: Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Meyer Squibb, Boehringer Ingelheim, MSD, Novartis, Amgen, Roche, Takeda, Janssen; Non-Financial Interests, Personal, Leadership Role: Swiss Academy for Clinical Cancer Research (SAKK); Non-Financial Interests, Personal, Principal Investigator, of clinical trials: Roche; Non-Financial Interests, Personal, Principal Investigator, Clinical Trials: Takeda, MSD, Bristol Meyer Squibb, Amgen. All other authors have declared no conflicts of interest.