Induction of a CD8 T cell intrinsic DNA damage and repair response is associated with clinical response to PD-1 blockade in uterine cancer.

Despite the success of immune checkpoint blockade (ICB), many patients fail to achieve durable clinical benefit, and the underlying immunological mechanisms remain poorly understood. Here, we investigated immune reinvigoration by ICB in advanced or recurrent hypermutated or microsatellite instability-high, mismatch repair deficient (MSI-H/MMRd) uterine cancer patients treated with anti-PD-1 (nivolumab). CD8 T cells underwent rapid pharmacodynamic proliferation 2-4 weeks after initiating PD-1 blockade. This immunological response, however, did not correlate with clinical response. We hypothesized that the T cell-intrinsic response to proliferative and genotoxic stress might contribute to the disparity between immunological and clinical response. We developed a high-dimensional single cell cytometric platform to simultaneously analyze T cell differentiation with changes in DNA damage and repair (DDR) pathways. This DDR-Immune platform revealed T cell subset-specific patterns of DDR, and distinct DDR pathways induced by different types of DNA damage. Applying this platform to MSI-H/MMRd or hypermutated uterine cancer patients revealed a signature of DDR exemplified by rapid increase in phosphorylated-ATM (pATM) intrinsic to CD8 T cells proliferating in response to PD-1 blockade that distinguished clinical responders and non-responders. ATM regulated transcriptional circuits in T cells were associated with better clinical response to PD-1 blockade. These findings highlight a previously unrecognized role for CD8 T cell-intrinsic DDR as a potential determinant of immune fitness and clinical outcome of PD-1 blockade therapy. ### Competing Interest Statement EJW is consulting or is an advisor for Merck, Marengo, Janssen, Related Sciences, Synthekine and Surface Oncology. EJW is a founder of Surface Oncology, Arsenal Biosciences and Danger Bio. EJW is an inventor on a patent (US Patent number 10,370,446) submitted by Emory University that covers the use of PD-1 blockade to treat infections and cancer. DAO is a consultant for Akoya Biosciences. CFF has a Steering Committee Membership (compensation waived) for Merck and Genentech. CFF is on the Advisory Board for AstraZeneca. CFF receives research support (to MSKCC) from Merck, BMS and Genentech. ACH is a consultant for Immunai. D.Z. reports institutional grants from Genentech, AstraZeneca, and Plexxikon, as well as personal fees from Genentech, AstraZeneca, Xencor, Memgen, Takeda, Synthekine, Immunos, and Calidi Biotherapeutics, outside of the submitted work. D.Z. is also an inventor on a patent related to the use of oncolytic Newcastle Disease Virus for cancer therapy.