期刊
CLINICAL CANCER RESEARCH
卷 26, 期 21, 页码 5689-5700出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-20-1065
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资金
- University of Florida Health Cancer Center Predoctoral Award
- American Brain Tumor Association Research Collaboration grant
- Alex's Lemonade Stand Young Investigator grant
- Florida Center for Brain Tumor Research grant
- Wells Foundation
- University of Florida Clinical and Translational Sciences Award [UL1TR001427]
Purpose: Immunotherapy has been demonstrably effective against multiple cancers, yet tumor escape is common. It remains unclear how brain tumors escape immunotherapy and how to overcome this immune escape. Experimental Design: We studied KR158B-luc glioma-bearing mice during treatment with adoptive cellular therapy (ACT) with polyclonal tumor-specific T cells. We tested the immunogenicity of primary and escaped tumors using T-cell restimulation assays. We used flow cytometry and RNA profiling of whole tumors to further define escape mechanisms. To treat immune-escaped tumors, we generated escape variant-specific T cells through the use of escape variant total tumor RNA and administered these cells as ACT. In addition, programmed cell death protein-1 (PD-1) checkpoint blockade was studied in combination with ACT. Results: Escape mechanisms included a shift in immunogenic tumor antigens, downregulation of MHC class I, and upregulation of checkpoint molecules. Polyclonal T cells specific for escape variants displayed greater recognition of escaped tumors than primary tumors. When administered as ACT, these T cells prolonged median survival of escape variant-bearing mice by 60%. The rational combination of ACT with PD-1 blockade prolonged median survival of escape variant glioma-bearing mice by 110% and was dependent upon natural killer cells and T cells. Conclusions: These findings suggest that the immune landscape of brain tumors are markedly different postimmunotherapy yet can still be targeted with immunotherapy.
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