PD-1 regulates tumor-infiltrating CD8+ T cells in both a cell-intrinsic and a cell-extrinsic fashion
Name
jem_20230542.pdf
Description
Published version
Size
10.27 MB
Format
Adobe PDF
Checksum (MD5)
0104e85a211430cc999fccdea937322c
Author(s)
Pauken, Kristen E
Markson, Samuel C
Conway, Thomas S
Juneja, Vikram R
Shahid, Osmaan
Burke, Kelly P
Rowe, Jared H
Nguyen, Thao H
Collier, Jenna L
Walsh, Jaclyn ML
Date Issued
October 6, 2025
Journal
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Citation
Kristen E. Pauken, Samuel C. Markson, Thomas S. Conway, Vikram R. Juneja, Osmaan Shahid, Kelly P. Burke, Jared H. Rowe, Thao H. Nguyen, Jenna L. Collier, Jaclyn M.L. Walsh, Megan E. Fung, Jacob M. Luber, Alison E. Ringel, Jason M. Schenkel, Gordon J. Freeman, Marcia C. Haigis, Meromit Singer, Arlene H. Sharpe; PD-1 regulates tumor-infiltrating CD8+ T cells in both a cell-intrinsic and a cell-extrinsic fashion. J Exp Med 6 October 2025; 222 (10): e20230542.
Version
Final published version
Abstract
Although PD-1 inhibitors are FDA-approved for over 25 different cancers, the mechanisms contributing to response remain incompletely understood. To investigate how PD-1–deleted CD8+ T cells influence PD-1–expressing CD8+ T cells in the same tumor microenvironment, we developed an inducible PD-1 knockout (KO) model in which PD-1 is deleted on ∼50% of cells. PD-1 deletion beginning at day 7 after implantation of MC38 tumor cells led to robust tumor control. Remarkably, PD-1–expressing CD8+ T cells in the tumor had increased functionality similar to PD-1 KO CD8+ T cells. Using single-cell RNA-seq and TCR-seq, we found that the major transcriptional changes following PD-1 deletion were shared by PD-1 KO and PD-1–expressing CD8+ T cells, although PD-1 KO clones preferentially expanded. These data suggest PD-1 inhibitors not only exert cell-intrinsic effects but also may promote increased T cell function through non–cell-autonomous mechanisms, which has important implications for design of PD-1–based cancer immunotherapies.
MIT Department
Broad Institute of MIT and Harvard
Harvard-MIT Program in Health Sciences and Technology
Koch Institute for Integrative Cancer Research at MIT
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1084/jem.20230542
