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J Exp Med. 2017 Apr 3;214(4):895-904. doi: 10.1084/jem.20160801. Epub 2017 Mar 16.

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

Author information

1
Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139.
2
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.
3
Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115.
4
Division of Medical Sciences, Harvard Medical School, Boston, MA 02115.
5
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
6
Division of Hematology/Oncology, Children's Hospital, Harvard Medical School, Boston, MA 02115.
7
Broad Institute of MIT and Harvard, Cambridge, MA 02142.
8
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
9
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115 arlene_sharpe@hms.harvard.edu.

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.

PMID:
28302645
PMCID:
PMC5379970
DOI:
10.1084/jem.20160801
[Indexed for MEDLINE]
Free PMC Article

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