Immune Escape After Adoptive T-cell Therapy for Malignant Gliomas.

Autor:	Wildes TJ; University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, Florida., Dyson KA; University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, Florida., Francis C; University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, Florida., Wummer B; University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, Florida., Yang C; University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, Florida., Yegorov O; University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, Florida., Shin D; University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, Florida., Grippin A; University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, Florida., Dean BD; University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, Florida., Abraham R; University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, Florida., Pham C; University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, Florida., Moore G; University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, Florida., Kuizon C; University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, Florida., Mitchell DA; University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, Florida., Flores CT; University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, Florida. catherine.flores@neurosurgery.ufl.edu.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2020 Nov 01; Vol. 26 (21), pp. 5689-5700. Date of Electronic Publication: 2020 Aug 11.
DOI:	10.1158/1078-0432.CCR-20-1065
Abstrakt:	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. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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