Back to Search Start Over

PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity

Authors :
Kathleen A. McGuire
Arlene H. Sharpe
W. Nicholas Haining
Robert T. Manguso
Natalie B. Collins
Martin W. LaFleur
Vikram R. Juneja
Gordon J. Freeman
Source :
The Journal of Experimental Medicine
Publication Year :
2017
Publisher :
The Rockefeller University Press, 2017.

Abstract

Both tumor- and host-derived PD-L1 can play critical roles in immunosuppression; differences in tumor immunogenicity appear to underlie their relative contributions. Juneja et al. show that in immunogenic MC38 tumors, PD-L1 on tumor cells dominates in suppressing tumor immunity by inhibiting CD8 T cell cytotoxicity.<br />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.

Details

Language :
English
ISSN :
15409538 and 00221007
Volume :
214
Issue :
4
Database :
OpenAIRE
Journal :
The Journal of Experimental Medicine
Accession number :
edsair.doi.dedup.....e5b8a064d171bb973b432601e08c4357