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Updated: Sep 14, 2025
Tumor Transplantation for Assessing the Dynamics of Tumor-Infiltrating CD8+ T Cells in Mice
Published on: June 12, 2021
PD-1 regulates tumor-infiltrating CD8+ T cells in both a cell-intrinsic and a cell-extrinsic fashion
Kristen E Pauken1,2, Samuel C Markson1,2,3, Thomas S Conway1,2
1Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
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.
Insights
Deleting programmed cell death protein 1 (PD-1) in some tumor-infiltrating CD8+ T cells boosts anti-cancer immunity. This enhances the function of both PD-1 deleted and remaining PD-1 expressing T cells, suggesting non-cell-autonomous effects.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Biology
Background:
- Programmed cell death protein 1 (PD-1) inhibitors are approved for over 25 cancers.
- Mechanisms of PD-1 inhibitor response are not fully understood.
Purpose of the Study:
- To investigate how PD-1 deleted CD8+ T cells influence PD-1 expressing CD8+ T cells within the same tumor microenvironment.
- To explore the non-cell-autonomous effects of PD-1 deletion on anti-tumor immunity.
Main Methods:
- Developed an inducible PD-1 knockout (KO) mouse model.
- Utilized MC38 tumor implantation and single-cell RNA sequencing (scRNA-seq) with TCR sequencing (TCR-seq).
Main Results:
- PD-1 deletion in approximately 50% of CD8+ T cells led to robust tumor control.
- PD-1 expressing CD8+ T cells exhibited increased functionality, similar to PD-1 KO cells.
- Shared transcriptional changes were observed in both PD-1 KO and PD-1 expressing CD8+ T cells, with preferential expansion of PD-1 KO clones.
Conclusions:
- PD-1 inhibitors may promote T cell function through non-cell-autonomous mechanisms, in addition to cell-intrinsic effects.
- Findings have implications for designing novel PD-1-based cancer immunotherapies.
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