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. 2025 Oct 6;222(10):e20230542.
doi: 10.1084/jem.20230542. Epub 2025 Jul 24.

PD-1 regulates tumor-infiltrating CD8+ T cells in both a cell-intrinsic and a cell-extrinsic fashion

Kristen E Pauken #  1   2 , Samuel C Markson #  1   2   3 , Thomas S Conway  1   2 , Vikram R Juneja  1   2   4 , Osmaan Shahid  1   2   5 , Kelly P Burke  1   2   6 , Jared H Rowe  1   2   7 , Thao H Nguyen  1   2 , Jenna L Collier  1   2 , Jaclyn M L Walsh  1   2   3   8 , Megan E Fung  1   2 , Jacob M Luber  3   5   9 , Alison E Ringel  10 , Jason M Schenkel  11   12 , Gordon J Freeman  6 , Marcia C Haigis  10 , Meromit Singer  1   3   5 , Arlene H Sharpe  1   2   3   12
Affiliations

PD-1 regulates tumor-infiltrating CD8+ T cells in both a cell-intrinsic and a cell-extrinsic fashion

Kristen E Pauken et al. J Exp Med. .

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.

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Conflict of interest statement

Disclosures: V.R. Juneja reported personal fees from BioNTech US, Inc. outside the submitted work. G.J. Freeman reported personal fees from iTeos, Nextpoint, IgM, GV20, Geode, BioEntre, Santa Ana Bio, and Simcere of America outside the submitted work; in addition, G.J. Freeman had a patent to the PD-L1/PD-1 pathway with royalties paid “Roche,” a patent to the PD-L1/PD-1 pathway with royalties paid “Merck MSD,” a patent to the PD-L1/PD-1 pathway with royalties paid “AstraZeneca,” a patent to the PD-L1/PD-1 pathway with royalties paid “Bristol-Myers Squibb,” a patent to the PD-L1/PD-1 pathway with royalties paid “Merck KGA,” a patent to the PD-L1/PD-1 pathway with royalties paid “Boehringer Ingelheim,” a patent to the PD-L1/PD-1 pathway licensed “Eli Lilly,” a patent to the PD-L1/PD-1 pathway licensed “Coherus Biosciences,” and a patent to the PD-L1/PD-1 pathway licensed “Novartis”; and has equity in Nextpoint, iTeos, Invaria, GV20, and Geode. M. Haigis reported grants from ReFuel Bio, personal fees from ReFuel Bio and Mito Q, and “other” from Celine Bio outside the submitted work. M. Singer reported personal fees from Guardant Health outside the submitted work; in addition, M. Singer had a patent to US 2022/0347278 A1 pending, a patent to WO 2019/068099 A1 pending, a patent to US 2019/0262399 A1 pending, a patent to WO 2018/049025 A3 pending, a patent to WO 2018/049025 A2 pending, a patent to US 2021/0263012 A1 pending, a patent to WO 2019/100001 A1 pending, a patent to US 2021/0130776 A1 pending, a patent to WO 2017/075478 A2 pending, a patent to EP 3368689 B1 pending, a patent to WO 2024/264065 A1 pending, a patent to WO 2017/075478 A3 pending, and a patent to WO 2017/075465 A1 pending. A.H. Sharpe reported grants from NIH P0156299, NIH P01AI108545, NIH P0139671, NIH P50 CA101942, NIH 7K08CA256044-3, NIH 5TL1TR002543, Fund for Innovation in Cancer Informatics, MD Anderson CPRIT Award, Andrew Sabin Family Foundation, American Association of Immunologists, and Cancer Research Institute during the conduct of the study; personal fees from Surface Oncology, Sq Biotech, Selecta, Elpiscience, Bicara, FibroGen, Alixia, GlaxoSmithKline, Janssen, Amgen, BioEntre, ImmVue, and AltruBio; grants from Merck, Quark Ventures, AbbVie, Moderna, Erasca, Vertex, TaiwanBio, Calico, and Yosemite; and “other” from Monopteros and Corner Therapeutics outside the submitted work; in addition, A.H. Sharpe had a patent number 7,432,059 with royalties paid “Roche, Merck, Bristol-Myers-Squibb, EMD-Serono, Boehringer Ingelheim, AstraZeneca, Leica, Mayo Clinic, Dako and Novartis,” a patent number 7,722,868 with royalties paid “Roche, Merck, Bristol-Myers-Squibb, EMD-Serono, Boehringer Ingelheim, AstraZeneca, Leica, Mayo Clinic, Dako and Novartis,” a patent number 8,652,465 licensed Roche, a patent number 9,457,080 licensed Roche, a patent number 9,683,048 licensed Novartis, a patent number 9,815,898 licensed Novartis, a patent number 9,845,356 licensed Novartis, a patent number 10,202,454 licensed Novartis, a patent number 10,457,733 licensed Novartis, a patent number 9,580,684 issued none, a patent number 9,988,452 issued none, a patent number 10,370,446 issued none, a patent number 10,457,733 issued none, a patent number 10,752,687 issued none, a patent number 10,851,165 issued none, a patent number 10,934,353 issued none, and a patent number 15,314,251 issued none; and is also on the scientific advisory boards of the Massachusetts General Cancer Center, Program in Cellular and Molecular Medicine at Boston Children’s Hospital, the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center, the Johns Hopkins Bloomberg–Kimmel Institute for Cancer Immunotherapy, the Gladstone Institutes, and Perlmutter Cancer Center at New York University and is an academic editor for the Journal of Experimental Medicine. K.E. Pauken reports a patent WO2017165412A3 that is pending. No other disclosures were reported.

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