Induction of a T Cell Intrinsic DNA Damage and Repair Response is Associated with Clinical Response to PD-1 Blockade
Thursday, June 23, 2022
4:00 PM – 4:15 PM PT
Location: Salons 1/2
Authors: Yuki Muroyama, n/a (Presenting Author) - Institute for Immunology, Perelman School of Medicine, University of Pennsylvania; Sasikanth Manne, n/a (Co-Author) - Institute for Immunology, Perelman School of Medicine, University of Pennsylvania; Nils Wellhausen, n/a (Co-Author) - Center for Cellular Immunotherapies, University of Pennsylvania, Perelman School of Medicine; Derek A. Oldridge, n/a (Co-Author) - Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia; Allison R. Greenplate, n/a (Co-Author) - Immune Health, University of Pennsylvania, Perelman School of Medicine; Lakshmi Chilukuri, n/a (Co-Author) - Institute for Immunology, Perelman School of Medicine, University of Pennsylvania; Divij Mathew, n/a (Co-Author) - Institute for Immunology, Perelman School of Medicine, University of Pennsylvania; Caiyue Xu, n/a (Co-Author) - Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania; Ramin Herati, n/a (Co-Author) - Department of Medicine, Grossman School of Medicine, New York University, New York; Alexander C. Huang, n/a (Co-Author) - Division of Hematology and Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania; Carl H. June, n/a (Co-Author) - Center for Cellular Immunotherapies, University of Pennsylvania, Perelman School of Medicine; Dmitriy Zamarin, n/a (Co-Author) - Department of Medicine, Memorial Sloan Kettering Cancer Center; Claire Friedman, n/a (Co-Author) - Department of Medicine, Memorial Sloan Kettering Cancer Center; E. John Wherry, n/a (Co-Author) - Institute for Immunology, Perelman School of Medicine, University of Pennsylvania
Despite the success of immune checkpoint blockade (ICB), many patients still fail to achieve durable clinical benefit, and the underlying immunological mechanisms of response versus progression remain poorly understood. Here, we investigated immune reinvigoration by ICB in chemotherapy-resistant hypermutated or microsatellite instability-high (MSI-H) uterine cancer patients treated with nivolumab. Upon initiation of treatment, CD8 T cells underwent rapid pharmacodynamic proliferation 2-4 weeks after starting PD-1 blockade. This immunological response, however, did not correlate with clinical response. We hypothesized that the T celI-intrinsic response to proliferative and genotoxic stress might contribute to the disparity between immunological and clinical response. To address this question, we developed a high-dimensional platform that enables simultaneous analysis of T cell differentiation state with changes in major DNA damage and repair (DDR) pathways at single cell resolution. This DDR-Immune platform revealed consistent T cell subset specific patterns of DDR, as well as specific DDR pathways induced by different types of DNA damage. Applying this DDR-Immune platform to MSI-H or hypermutated uterine cancer patients revealed a signature of DDR exemplified by rapid increase in phosphorylated-ATM (pATM) intrinsic to proliferating CD8 T cells that distinguished clinical responders and non-responders. Furthermore, transcriptional analysis with CRISPR knockout of ATM in human T cells suggested that the ability to induce ATM regulated transcriptional circuits in T cells upon PD-1 blockade is associated with better clinical response. These findings highlight a previously unrecognized role for T cell-intrinsic DDR as a potential determinant of immune fitness and clinical outcome to PD-1 blockade therapy.