Temporally Distinct PD-L1 Expression by Tumor and Host Cells Contributes to Immune Escape

作者：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 · 发表于：Cancer Immunology Research · 年份：2017 · DOI：10.1158/2326-6066.cir-16-0391 · 被引用次数：324 · 研究领域：Cancer Immunotherapy and Biomarkers、Immunotherapy and Immune Responses、Immune Cell Function and Interaction

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 tumor-associated macrophages (TAM), was also important for tumor immune escape. We demonstrated that induction of PD-L1 on tumor cells was IFNγ-dependent and transient, but PD-L1 induction on TAMs was of greater magnitude, only partially IFNγ dependent, and was stable over time. Thus, PD-L1 expression on either tumor cells or host immune cells could lead to tumor escape from immune control, indicating that total PD-L1 express...