Temporally distinct PD-L1 expression by tumor and host cells contributes to immune escape

Takuro Noguchi, Jeffrey P. Ward, Matthew M. Gubin, Cora D. Arthur, Sang Hun Lee, Jasreet Hundal, Mark J. Selby, Robert F. Graziano, Elaine R. Mardis, Alan J. Korman, Robert D. Schreiber

Research output: Contribution to journalArticlepeer-review

154 Scopus citations

Abstract

Antibody blockade of programmed death-1 (PD-1) or its ligand, PD-L1, has led to unprecedented therapeutic responses in certain tumor-bearing individuals, but PD-L1 expression's prognostic value in stratifying cancer patients for such treatment remains unclear. Reports conflict on the significance of correlations between PD-L1 on tumor cells and positive clinical outcomes to PD-1/PD-L1 blockade. We investigated this issue using genomically related, clonal subsets from the same methylcholanthrene-induced sarcoma: a highly immunogenic subset that is spontaneously eliminated in vivo by adaptive immunity and a less immunogenic subset that forms tumors in immunocompetent mice, but is sensitive to PD-1/PD-L1 blockade therapy. Using CRISPR/Cas9-induced loss-of-function approaches and overexpression gain-of-function techniques, we confirmed that PD-L1 on tumor cells is key to promoting tumor escape. In addition, the capacity of PD-L1 to suppress antitumor responses was inversely proportional to tumor cell antigenicity. PD-L1 expression on host cells, particularly tumorassociated macrophages (TAM), was also important for tumor immune escape. We demonstrated that induction of PD-L1 on tumor cells was IFNg-dependent and transient, but PD-L1 induction on TAMs was of greater magnitude, only partially IFNg dependent, and was stable over time. Thus, PD-L1 expression on either tumor cells or host immune cells could lead to tumor escape fromimmune control, indicating that total PD-L1 expression in the immediate tumor microenvironment may represent a more accurate biomarker for predicting response to PD-1/PD-L1 blockade therapy, compared with monitoring PD-L1 expression on tumor cells alone.

Original languageEnglish
Pages (from-to)106-117
Number of pages12
JournalCancer immunology research
Volume5
Issue number2
DOIs
StatePublished - Feb 2017

Fingerprint

Dive into the research topics of 'Temporally distinct PD-L1 expression by tumor and host cells contributes to immune escape'. Together they form a unique fingerprint.

Cite this