LAUSR

Immune checkpoint blockade (ICT) has provided robust, durable responses to a subset of patients. Many initial ICT trials were focused on highly mutated cancer types, such as melanoma and lung cancer, largely predicated on the idea that mutation-derived neoantigens would allow for generation of tumor-specific T cells. Subsequent analysis of patient responses in these highly mutated cancer types confirmed that increased tumor mutation burden (TMB) corresponded with improved patient outcomes. Further clinical studies identified additional predictive biomarkers, such as PD-L1 protein expression, and various gene expression signatures. Based on the success of ICT in hypermutated cancer types, further clinical trials with ICT were performed in cancers with overall lower mutational burden. These studies have indicated that many non-hypermutated cancer types with relatively low TMB may be effectively treated with ICT. For example, patients with clear cell renal cell carcinoma (ccRCC) display relatively low TMB overall, and a narrow distribution of TMB across patients, yet clinical response rates to ICT are ~30%, with some durable responses seen. Other tumor types with minimal mutation burdens, including glioblastoma (GBM) and triple negative breast cancer (TNBC), have likewise shown encouraging clinical responses to ICT. We recently demonstrated distinct tumor immunobiology between hypermutated and non-hypermutated tumor types, notably that relative neoantigen load/tumor mutation burden was only a relevant factor for immune infiltration in hypermutated tumor types. Consistent with this, clinical trials have demonstrated that TMB does not predict response to ICT in tumor types with minimal mutational load, such as breast cancer, ccRCC, and GBM. Thus, there remains a critical gap in knowledge as to how to identify which patients with non-hypermutated cancer may benefit from ICT. Here, we demonstrate that a replication stress response (RSR) defect gene expression signature accurately predicts ICT response in 11 independent non-hypermutated patient cohorts from 6 tumor types for which other biomarkers failed. Pre-clinical studies indicate that aberrant origin firing in RSR deficient tumor cells causes exhaustion of replication protein A, resulting in accumulation of immunostimulatory cytosolic DNA. Induction or suppression of RSR deficiencies was sufficient to modulate response to ICT. Taken together, the RSR defect gene signature can accurately identify patients who will benefit from ICT across numerous non-hypermutated tumor types, and pharmacological induction of RSR defects may further expand the benefits of ICT to more patients. Citation Format: D McGrail, P Pilie, XHF Zhang, J Rosen, L Voorwerk, M Kok, A Heimberger, C Peterson, E Jonasch, S Lin. Replication stress response defects predict responses to ICT in non-hypermutated tumors [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP084.