Abstract 573: Mutations found by targeted next generation sequencing is associated with intra-tumor immune profile and may predict response to anti-PD1 therapy in lung adenocarcinoma

Abstract

Abstract Purpose: the immune environment of cancer is the target of immunotherapies with programmed cell death 1 (PD-1) therapeutic antibodies. However, factors that can robustly predict long-lasting responses are still needed. Previous studies showed a role of cancer cells on immune response setting, but the impact of somatic mutations on the composition of the immune stroma is not fully characterized. Experimental Design: We characterized the immune profile of 221 lung adenocarcinomas using immunohistochemistry (CD8 T cells, Macrophages, neutrophils, PD-L1) and compare to tumor mutational status using targeted next-generation sequencing. The response to PD-1 blockers was analyzed from a prospective cohort of 31 lung carcinomas according to tumor mutational profiles and to tumor cell PD-L1 expression. Results: We report that distinct combinations of STK11, EGFR and TP53 mutations, allows the identification of immune cells combination and prediction of PD-L1 expression on tumor cells. Lung adenocarcinomas with the highest CD8 T cell density and PD-L1 expression were those with TP53 mutations without co-occurring STK11or EGFR alterations (TP53-mut/STK11-EGFR-WT), and independently of KRAS status. Interestingly in TP53-mut/STK11-EGFR-WT tumors, pathways related to T cell chemotaxis, immune cell cytotoxicity, and antigen processing were up-regulated. In accordance with these results we found a prolonged progression-free survival (PFS: HR=0.32; 95% CI, 0.16-0.63, p<0.001) in anti-PD-1 treated patients harboring TP53-mut/STK11-EGFR-WT tumors. This clinical benefit was even more remarkable in patients with associated strong PD-L1 expression. Conclusions: Our study reveals that mutations in lung adenocarcinoma impact intra-tumor immune profile and predict response to PD-1 blockade. Citation Format: Audrey Lupo, Jerome Biton, Marco Alifano, Diane Damotte, Jennifer Arrondeau, Pascaline Boudou, François Goldwasser, Karen Leroy, Marie Wislez, Pierre Laurent-Puig, Isabelle Cremer, Helène Blons, Ronald Herbst. Mutations found by targeted next generation sequencing is associated with intra-tumor immune profile and may predict response to anti-PD1 therapy in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 573.