• 肺原位或皮下接种小鼠肺癌细胞(CMT167和LLC);
  • 抗PD-1/PD-L1治疗对CMT167原位肿瘤的抑制率达95%,对皮下移植瘤的抑制率30%,LLC的原位肿瘤的抑制率为35%;
  • 皮下CMT167肿瘤Foxp3+CD4+ T细胞更高,PD-1+CD4+T细胞更少,CMT167原位肿瘤的微环境中携带PD-L1(高)细胞的丰度增加;
  • 在CMT167 细胞内沉默PD-L1,致原位肿瘤缩小且抗PD-L1治疗仍敏感,将CMT167细胞植入PD-L1-小鼠阻断原位肿瘤生长,提示PD-L1在肿瘤细胞及微环境中均起作用。

The Tumor Microenvironment Regulates Sensitivity of Murine Lung Tumors to PD-1/PDL1 Antibody Blockade



2017-08-17, Article

Abstract & Authors:展开

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 pre-clinical 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 to CMT167 orthotopic tumors. Flow cytometric analysis also demonstrated increased abundance of PD-L1(high) cells in the tumor microenvironment in CMT167 tumor-bearing lungs compared to 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.

First Authors:
Howard Y Li

Correspondence Authors:
Raphael A Nemenoff

All Authors:
Howard Y Li,Maria McSharry,Bonnie Bullock,Teresa T Nguyen,Jeff Kwak,Joanna M Poczobutt,Trisha R Sippel,Lynn E Heasley,Mary C Weiser-Evans,Eric T Clambey,Raphael A Nemenoff