PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity
Abstract
It is unclear whether PD-L1 on tumor cells is sufficient for tumor immune evasion or simply correlates with an inflamed tumor microenvironment. We used three mouse tumor models sensitive to PD-1 blockade to evaluate the significance of PD-L1 on tumor versus nontumor cells. PD-L1 on nontumor cells is critical for inhibiting antitumor immunity in B16 melanoma and a genetically engineered melanoma. In contrast, PD-L1 on MC38 colorectal adenocarcinoma cells is sufficient to suppress antitumor immunity, as deletion of PD-L1 on highly immunogenic MC38 tumor cells allows effective antitumor immunity. MC38-derived PD-L1 potently inhibited CD8+ T cell cytotoxicity. Wild-type MC38 cells outcompeted PD-L1–deleted MC38 cells in vivo, demonstrating tumor PD-L1 confers a selective advantage. Thus, both tumor- and host-derived PD-L1 can play critical roles in immunosuppression. Differences in tumor immunogenicity appear to underlie their relative importance. Our findings establish reduced cytotoxicity as a key mechanism by which tumor PD-L1 suppresses antitumor immunity and demonstrate that tumor PD-L1 is not just a marker of suppressed antitumor immunity.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 16, 2017
- Source ID
- 10.1084/jem.20160801
Entities
People
- Arlene Sharpe
- Gordon J. Freeman
- Kathleen A. Mcguire
- Martin W. Lafleur
- Natalie Collins
- Robert T. Manguso
- Vikram R. Juneja
- W. Nicholas Haining
Organizations
- Broad Institute
- Cancer Research Institute
- Dana–Farber Cancer Institute
- Harvard Medical School
- Harvard–MIT Division of Health Sciences and Technology
- National Institutes of Health
- National Science Foundation
- United States Department of Defense