Immune checkpoint inhibitors targeting the interaction between programmed cell death-1 (PD-1) and its
ligand PD-L1 induce
tumor regression in a subset of
non-small cell lung cancer patients. However, clinical response rates are less than 25%. Evaluation of combinations of
immunotherapy with existing
therapies requires appropriate preclinical animal models. In this study, murine
lung cancer cells (CMT167 and LLC) were implanted either orthotopically in the lung or subcutaneously in syngeneic mice, and response to anti-PD-1/PD-L1
therapy was determined. Anti-PD-1/PD-L1
therapy inhibited CMT167 orthotopic lung
tumors by 95%. The same treatments inhibited CMT167 subcutaneous
tumors by only 30% and LLC orthotopic lung
tumors by 35%. CMT167 subcutaneous
tumors had more Foxp3+ CD4+ T cells and fewer PD-1+ CD4+ T cells compared with CMT167 orthotopic
tumors. Flow cytometric analysis also demonstrated increased abundance of PD-L1high cells in the tumor microenvironment in CMT167
tumor-bearing lungs compared with CMT167 subcutaneous
tumors or LLC
tumor-bearing lungs. Silencing PD-L1 expression in CMT167 cells resulted in smaller orthotopic
tumors that remained sensitive to anti-PD-L1
therapy, whereas implantation of CMT167 cells into PD-L1- mice blocked orthotopic
tumor growth, indicating a role for PD-L1 in both the
cancer cell and the microenvironment. These findings indicate that the response of
cancer cells to
immunotherapy will be determined by both intrinsic properties of the
cancer cells and specific interactions with the microenvironment. Experimental models that accurately recapitulate the lung tumor microenvironment are useful for evaluation of immunotherapeutic agents.
Cancer Immunol Res; 5(9); 767-77. ©2017 AACR.