Abstract 6543: Comparative analysis of immune landscape according to EGFR mutation and tumor PD-L1 proportion scores in non-small cell lung cancer at single cell resolution

Abstract

Abstract Introduction: In EGFR-mutant non-small cell lung cancer (NSCLC), the efficacy of immune checkpoint blockade (ICB) is limited with higher incidence of toxicity profiles. EGFR-mutant NSCLC is associated with immune suppressive microenvironment, including lower programmed death-ligand 1 (PD-L1), tumor mutational burden (TMB), and tumor-infiltrating CD8+ T lymphocytes. However, tumors expressing high levels of PD-L1 show improved and durable clinical benefit in immunotherapy. In addition, Understanding the dynamics of tumor microenvironment may elucidate immune response in terms of immune composition, and help overcome resistance to immune checkpoint inhibitors. Here, we demonstrate that conventional type 1 dendritic cells (cDC1s) is one of the key tumor microenvironment, resulting in priming of CD8+ T cells and production of chemokines, such as CXCL9/CXCL10 and cytokines that augment anti-tumor immunity. Methods: A total of 31 surgical samples of NSCLC, including EGFR wild and mutant NSCLC of stages I-III, and 16 normal lung tissue samples were collected. PD-L1 expression in EGFR wild type was categorized into tumor proportion score (TPS) of < 50% and ≥ 50% using immunohistochemistry (IHC). Single cell RNA sequencing was performed with the Scanpy toolkit on the retrospective cohorts of normal (n=16), EGFR mutant (n=14, L858R=6, E19Del=8), EGFR wild TPS ≥ 50% (n=10), and TPS < 50% (n=7). Results: We observed that an overall tumor specific immune response occurred in EGFR wild-type TPS ≥ 50% compared with others. XCL1+ innate-like T cells, which act as an orchestra of tumor specific immune response, were found. These cells had high expression of FCER1G and IL2RB, a receptor for IL-15, However, expression of CD8A/B, CD4 and FCGR3A was low. Interestingly, in these innate-like T cells, the expression of ITGAE, which interacts with E-cadherin in cancer cells, and CD81, which interacts with CD3 and enhances immunological synapse, was observed in EGFR wild TPS ≥ 50%. According to these results, XCR1+ cDC1s were enriched in EGFR wild-type TPS ≥ 50%. CXCL9/CXCL10, which recruits CXCR3+ effector T cells which are primed at the lymph node, was highly expressed in activated DCs at EGFR wild TPS ≥ 50%. CD8+ T cells were significantly enriched in EGFR wild-type TPS ≥ 50%. These cells also expressed IFNG and FLT3LG, which maintain the function of intra-tumoral dendritic cells (DCs), and were also up-regulated in EGFR wild-type TPS ≥ 50%. Among them, exhausted CD8+ T cells expressing PDCD1 were observed in EGFR wild TPS ≥ 50%, and these cells also expressed ITGAE and CD81. In addition, these cells also showed high expression of CXCR3, a receptor for CXCL9/CXCL10 which were expressed in the activated DCs. Conclusion: cDC1s-mediated tumor specific immune response occurred in patients with EGFR wild TPS ≥ 50%, which could be an important mechanism to predict anti-PD-1 response. Citation Format: YoungJoon Park, Su-Jin Choi, Jii Bum Lee, Dong Kwon Kim, Sun Min Lim, Seong Gu Heo, Ke Jia Qi, Byoung Chul Cho, Kyoung-Ho Pyo. Comparative analysis of immune landscape according to EGFR mutation and tumor PD-L1 proportion scores in non-small cell lung cancer at single cell resolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6543.