Abstract B027: ATR inhibition upregulates PD-L1 and potentiates the antitumor immune response to chemoimmunotherapy in small-cell lung cancer

Abstract

Abstract Introduction: Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer, with a very poor prognosis and limited therapeutic options. Recent clinical trials of immune checkpoint blockade (ICB) combined with chemotherapy delivered only very modest benefit. Here, we identified that ataxia telangiectasia and rad3 related (ATR), the primary activator of the replication stress response, is highly enriched in SCLC and inhibition of ATR induced DNA damage and apoptosis in multiple SCLC models. Methods: In this study, we performed genetic and pharmacological inhibition of ATR in a panel of human and murine SCLC models. Furthermore, we investigated the effect of ATR inhibition either alone or in combination with PD-L1 blockade either as a first-line or a second-line treatment in multiple immunocompetent mouse models of SCLC. The downstream effects of ATR inhibition was assessed by single-cell RNA sequencing, multicolor flow cytometry, western blot analysis, IHC, and genomic analysis. Results: In multiple immunocompetent SCLC mouse models, ATR inhibition (ATRi) remarkably enhanced the anti-tumor effect of PD-L1 blockade. We next tested the ATR inhibition either alone or in combination with PD-L1 in the second-line regimen for SCLC. We observed that ATR inhibition in combination with PD-L1 blockade significantly reduced tumor volume and prolonged survival of aggressive mice models when compared to PD-L1 alone. Targeting ATR enhanced the expression of PD-L1, activated the cGAS/STING pathway, induced the expression of Type I and II interferon pathways, and caused significant infiltration of cytotoxic and memory/effector T-cells into tumors. Interestingly, ATRi also led to significant induction of MHC class I in SCLC in vitro and in vivo models. Analysis of pre- and post-treatment clinical samples from a proof-of-concept study of a first-in-class ATR inhibitor, M6620 (VX970, berzosertib), and TOP1 inhibitor topotecan, in patients with relapsed SCLCs validated the induction of MHC class I and interferon pathway genes, for the first time in this disease. Conclusion: Our findings highlight ATRi as a potentially transformative vulnerability of SCLC, paving the way for combination clinical trials with anti-PD-L1. Given the increasing importance of immunotherapy for the management of SCLC and that ATR inhibitors are already in clinical trials, combining an ATR inhibitor with PD-L1 blockade may offer a particularly attractive strategy for the treatment of SCLC and contribute to the rapid translation of this combination into the clinic. Citation Format: Triparna Sen. ATR inhibition upregulates PD-L1 and potentiates the antitumor immune response to chemoimmunotherapy in small-cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B027.