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 M L, Fung Megan E, Luber Jacob M, Ringel Alison E, Schenkel Jason M, Freeman Gordon J, Haigis Marcia C, Singer Meromit, Sharpe Arlene H
Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School , Boston, MA, USA.
J Exp Med. 2025 Oct 6;222(10). doi: 10.1084/jem.20230542. Epub 2025 Jul 24.
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.
尽管PD-1抑制剂已获美国食品药品监督管理局（FDA）批准用于超过25种不同癌症，但导致应答的机制仍未完全明确。为了研究在同一肿瘤微环境中，缺失PD-1的CD8⁺ T细胞如何影响表达PD-1的CD8⁺ T细胞，我们构建了一种诱导型PD-1基因敲除（KO）模型，其中约50%的细胞中PD-1被敲除。在植入MC38肿瘤细胞后第7天开始敲除PD-1可实现对肿瘤的有效控制。值得注意的是，肿瘤中表达PD-1的CD8⁺ T细胞的功能增强，与PD-1基因敲除的CD8⁺ T细胞类似。通过单细胞RNA测序和TCR测序，我们发现PD-1基因敲除后主要的转录变化在PD-1基因敲除的CD
