Th165 - Induction of a T Cell Intrinsic DNA Damage and Repair Response is Associated with Clinical Response to PD-1 Blockade

Thursday, June 23, 2022

6:15 PM – 7:30 PM PT

Presenting Author(s)

YM

Yuki Muroyama, MD, PhD, n/a

Institute for Immunology, Perelman School of Medicine, University of Pennsylvania
Philadelphia, Pennsylvania, United States

Co-Author(s)

SM

Sasikanth Manne, n/a

Research Specialist
Institute for Immunology, Perelman School of Medicine, University of Pennsylvania
Philadelphia, Pennsylvania, United States
NW

Nils Wellhausen, n/a

Center for Cellular Immunotherapies, University of Pennsylvania, Perelman School of Medicine
Philadelphia, Pennsylvania, United States
DO

Derek A. Oldridge, MD, PhD, n/a

Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
AG

Allison R. Greenplate, PhD, n/a

Immune Health, University of Pennsylvania, Perelman School of Medicine
Philadelphia, Pennsylvania, United States
LC

Lakshmi Chilukuri, n/a

Institute for Immunology, Perelman School of Medicine, University of Pennsylvania
Philadelphia, Pennsylvania, United States
DM

Divij Mathew, PhD, n/a

Institute for Immunology, Perelman School of Medicine, University of Pennsylvania
Philadelphia, Pennsylvania, United States
CX

Caiyue Xu, n/a

Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania
Philadelphia, Pennsylvania, United States
RH

Ramin Herati, MD, n/a

Department of Medicine, Grossman School of Medicine, New York University, New York
New York, New York, United States
AH

Alexander C. Huang, MD, n/a

Division of Hematology and Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania
Philadelphia, Pennsylvania, United States
Carl H. June, MD, n/a

Director, Center for Cellular Immunotherapies Director, Parker Institute for Cancer Immunotherapy Professor of Pathology and Laboratory Medicine
Center for Cellular Immunotherapies, University of Pennsylvania, Perelman School of Medicine
Philadelphia, Pennsylvania, United States
DZ

Dmitriy Zamarin, MD, PhD, n/a

Department of Medicine, Memorial Sloan Kettering Cancer Center
New York, New York, United States
CF

Claire Friedman, MD, n/a

Department of Medicine, Memorial Sloan Kettering Cancer Center
New York, New York, United States
EW

E. John John. Wherry, PhD, n/a

Institute for Immunology, Perelman School of Medicine, University of Pennsylvania
Philadelphia, Pennsylvania, United States

Abstract Text: 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.