Abstract 2147: Radiosensitization via ATM inhibition in small cell lung cancer leads to increased immunogenicity and tumor infiltration

Abstract Purpose: Small cell lung cancer (SCLC) is an aggressive form of lung cancer with a dismal survival. PD-1/PD-L1 inhibitors have improved survival outcomes, but many patients fail to respond possibly due to a lack of T cell infiltration. Ionizing radiation (IR) activates innate regulatory genes through micronuclei formation and cGAS-STING upregulation. A previous in vitro dropout CRISPR screen has identified ATM as a top-ranked determinant of radiosensitization in SCLC cell-lines. Evaluation of ATM inhibition (ATMi) in combination with IR increases tumour T cell immunogenicity through a cGAS-STING-mediated mechanism. Methods and Materials: We investigated the combination of ATMi (AZD1390) and IR in SCLC cell-lines SBC5 and SHP77, to determine the synergism of cGAS-STING activation via immunofluorescence. Chemokine and cytokine expression following combination treatment was probed by qPCR and surface expression of PDL1 and HLA class I was quantified through flow cytometry. In the SCLC syngeneic mice, we evaluated the efficacy and immune-sensitizing effects of a triple combination of ATMi, RT and anti-PDL1 (ATMi+IR+ICB). Results: ATMi plus IR (ATMi+IR) lead to a significant (p < 0.001) increase of micronuclei frequency and cGAS micronuclei translocation relative to RT alone. ATMi+IR also resulted in a significant increase in CCL5 and CXCL10 expression compared to IR alone in SBC5 (FC = 6 and 1.5, respectively) and SHP77 (FC = 1.5 and 2, respectively). This phenotype was partially abrogated in cGAS knockout in SBC5 and H1048 cell-lines. Surface PDL1 increased by a FC of 3 in H82 in ATMi+IR relative to IR, while no change in surface HLA was observed. Within the KP1 syngeneic SCLC murine model, ATMi+IR+ICB led to a significant increase (p-value < 0.001) in T cell (CD45+CD3+) infiltration at day 12 relative to ATMi+IR. Interestingly, ATMi+IR had no change in T cell infiltration relative to both IR alone and IR plus anti-PDL1. Although an increase in T cell infiltration was observed, there was no additional benefit in tumour control of ATMi+IR+ICB compared to ATMi+IR. Conclusions: In this study, we demonstrated pharmacological inhibition of ATM enhanced SCLC chemokine expression in a cGAS-STING-dependent manner. We further validated this phenotype in a syngeneic SCLC murine model. Despite this marked improvement in SCLC T cell infiltration no further benefits was observed. Further studies are required to understand this lack of benefit. Citation Format: Bell Wu, Xiaozhuo Ran, Mary Shi, Lifang Song, Vivek Philip, Ming-Sound Tsao, Benjamin Lok. Radiosensitization via ATM inhibition in small cell lung cancer leads to increased immunogenicity and tumor infiltration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2147.