PD-1 regulates tumor-infiltrating CD8+ T cells in both a cell-intrinsic and a cell-extrinsic fashion
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.
Authors
- Jacob M. Luber (ORCID: https://orcid.org/0000-0001-5268-5732)
- Vikram R. Juneja (ORCID: https://orcid.org/0000-0001-6011-6417)
- Kristen E. Pauken (ORCID: https://orcid.org/0000-0002-4309-7880)
- Thao H. Nguyen (ORCID: https://orcid.org/0000-0002-2767-0528)
- Arlene H. Sharpe (ORCID: https://orcid.org/0000-0002-9736-2109)
- Meromit Singer (ORCID: https://orcid.org/0000-0002-1755-3598)
- Jenna L. Collier (ORCID: https://orcid.org/0000-0002-4071-4986)
- Marcia C. Haigis (ORCID: https://orcid.org/0000-0003-2530-2681)
- Kelly P. Burke (ORCID: https://orcid.org/0000-0003-2187-0147)
- Samuel C. Markson (ORCID: https://orcid.org/0000-0001-9053-9867)
- Alison E. Ringel (ORCID: https://orcid.org/0000-0002-6451-9376)
- Osmaan Shahid (ORCID: https://orcid.org/0000-0002-3694-8480)
- Megan E. Fung (ORCID: https://orcid.org/0000-0002-9053-0915)
- Gordon J. Freeman (ORCID: https://orcid.org/0000-0002-7210-5616)
- Jason M. Schenkel (ORCID: https://orcid.org/0000-0003-4641-6872)
- Thomas S. Conway (ORCID: https://orcid.org/0009-0006-9757-5995)
- Jared H. Rowe (ORCID: https://orcid.org/0000-0002-4223-4433)
- Jaclyn M. Long (ORCID: https://orcid.org/0000-0001-6292-1006)
Institutions
- Broad Institute (US)
- Twitter (United States) (US)
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Boston Biomedical Research Institute (US)
- Harvard University (US)
- Harvard–MIT Division of Health Sciences and Technology (US)
- Dana-Farber Cancer Institute (US)
- Harvard Stem Cell Institute (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2025-07-24
- DOI
- https://doi.org/10.1084/jem.20230542
- Citations
- 5
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 5.23
Funders
- Cancer Research Institute
- American Association of Immunologists
- Cancer Prevention and Research Institute of Texas
- Andrew Sabin Family Foundation
- Fund for Innovation in Cancer Informatics
- National Institutes of Health