Background: Anti-PD-1/PD-L1 immunotherapy is widely used to treat patients with advanced non-small-cell lung cancer (NSCLC). Although PD-1/PD-L1 inhibitor efficacy across NSCLC is now better understood, it is largely unknown how the tumor immune microenvironment differs regarding tumor genomics and its impact on prognosis and response to immunotherapy in East-Asian NSCLC patients.

Methods: We performed an integrated analysis on publicly available data to explore associations between anti-PD-1/PD-L1 immunotherapy efficacy and classic driver oncogene mutations, including EGFR, KRAS, and ALK fusion mutations, in East-Asian NSCLC patients. Four pooled and clinical cohort analyses were used to correlate driver oncogene mutation status and tumor microenvironment based on PD-L1 and CD8+ tumor-infiltrating lymphocytes (TILs). Immune infiltrating patterns were also established for genomic NSCLC subgroups by CIBERSORT algorithm.

Results: Based on East-Asian NSCLC patients, TIDE analysis revealed that for anti-PD-1/PD-L1 immunotherapy, EGFR-mutant and ALK-rearranged tumors may yield inferior responses; however, KRAS-mutant tumors may respond better. Pooled and clinical cohort analyses demonstrated tumor immune microenvironment heterogeneity with oncogenic addiction. Data showed remarkably higher PD-L1- and TIL-positive KRAS-mutant tumors, suggesting KRAS mutations may drive an inflammatory phenotype with adaptive immune resistance. However, the EGFR-mutant or ALK-rearranged groups showed a remarkably higher proportion of PD-L1/TIL tumors, suggesting an uninflamed phenotype with immunological ignorance. Notably, similar to triple wild-type NSCLC, EGFR L858R-mutant tumors positively correlated with an inflammatory phenotype, suggesting responsiveness to anti-PD-1/PD-L1 immunotherapy. Furthermore, CIBERSORT algorithm results revealed that apart from enriched CD8+ T cells, KRAS-mutant NSCLC showed a similar intratumoral immune profile to triple wild-type NSCLC. Strikingly, EGFR-mutant and ALK-rearranged tumors were characterized by enriched resting memory CD4+ T cells, as well as a lack of CD8+ and activated memory CD4+ T cells.

Conclusion: Our study highlights the complex relationship between immune heterogeneity and immunotherapeutic response in East-Asian NSCLC patients regarding oncogenic addiction. Importantly, our findings provide support for individualized treatments according to NSCLC molecular subtype.

Keywords: NSCLC, East-Asian, oncogene mutations, PD-1/PD-L1 inhibitors, immune landscape

Citation Format: Chengming Liu, Runsen Jin, Sufei Zheng, Xinfeng Wang, Nan Sun, Jie He. Molecular heterogeneity of anti-PD-1/PD-L1 immunotherapy efficacy is correlated with tumor immune microenvironment in non-small cell lung cancer from East-Asian patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3276.