期刊
CANCER IMMUNOLOGY RESEARCH
卷 9, 期 8, 页码 877-890出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-20-0785
关键词
-
资金
- NIH [K12 CA076931, K08 CA241084, R01 CA229803]
- Parker Institute for Cancer Immunotherapy
The study focused on T-cell surveillance of murine pancreatic adenocarcinoma cells expressing neoantigen and found that immune escape can occur in a tissue-specific manner. Tumor outgrowth in the pancreas and peritoneum was associated with reduced CD8T-cell priming by cDC1, which could be restored through CD40 agonist treatment. This highlights the importance of addressing microenvironmental barriers for successful combination immunotherapies.
T-cell recognition of tumor neoantigens is critical for cancer immune surveillance and the efficacy of immunotherapy. Tumors can evade host immunity by altering their antigenicity or orchestrating an immunosuppressive microenvironment, leading to outgrowth of poorly immunogenic tumors through the well-established process of cancer immunoediting. Whether cancer immune surveillance and immunoediting depend on the tissue site of origin, however, is poorly understood. Herein, we studied T-cell-mediated surveillance of antigenic, clonal murine pancreatic adenocarcinoma cells expressing neoantigen. Whereas such tumors are robustly eliminated after subcutaneous or intravenous challenge, we observed selective immune escape within the pancreas and peritoneum. Tumor outgrowth occurred in the absence of immunoediting, and antitumor immunity could not be rescued by PD-1 or CTLA-4 checkpoint blockade. Instead, tumor escape was associated with diminished CD8thorn T-cell priming by type I conventional dendritic cells (cDC1). Enhancing cDC1 cross-presentation by CD40 agonist treatment restored immunologic control by promoting T-cell priming and broadening T-cell responses through epitope spread. These findings demonstrate that immune escape of highly antigenic tumors can occur without immunoediting in a tissue-restricted manner and highlight barriers to cDC1-mediated T-cell priming imposed by certain microenvironments that must be addressed for successful combination immunotherapies.
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