Transfer of Allogeneic CD4+ T Cells Rescues CD8+ T Cells in Anti-PD-L1-Resistant Tumors Leading to Tumor Eradication.

Autor:	Arina A; Department of Pathology, The University of Chicago, Chicago, Illinois. aarina@bsd.uchicago.edu., Karrison T; Department of Health Studies, The University of Chicago, Chicago, Illinois., Galka E; Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois., Schreiber K; Department of Pathology, The University of Chicago, Chicago, Illinois., Weichselbaum RR; Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois., Schreiber H; Department of Pathology, The University of Chicago, Chicago, Illinois.
Jazyk:	angličtina
Zdroj:	Cancer immunology research [Cancer Immunol Res] 2017 Feb; Vol. 5 (2), pp. 127-136. Date of Electronic Publication: 2017 Jan 11.
DOI:	10.1158/2326-6066.CIR-16-0293
Abstrakt:	Adoptively transferred CD8 + T cells can stabilize the size of solid tumors over long periods of time by exclusively recognizing antigen cross-presented on tumor stroma. However, these tumors eventually escape T-cell-mediated growth control. The aim of this study was to eradicate such persistent cancers. In our model, the SIYRYYGL antigen is expressed by cancer cells that lack the MHC-I molecule K b needed for direct presentation, but the antigen is picked up and cross-presented by tumor stroma. A single injection of antigen-specific 2C CD8 + T cells caused long-term inhibition of tumor growth, but without further intervention, tumors started to progress after approximately 3 months. Escape was associated with reduced numbers of circulating 2C cells. Tumor-infiltrating 2C cells produced significantly less TNFα and expressed more of the "exhaustion" markers PD-1 and Tim-3 than T cells from lymphoid organs. High-dose local ionizing radiation, depletion of myeloid-derived suppressor cells, infusions of additional 2C cells, and antibodies blocking PD-L1 did not prevent tumor escape. In contrast, adoptive transfer of allogeneic CD4 + T cells restored the numbers of circulating Ag-specific CD8 + T cells and their intratumoral function, resulting in tumor eradication. These CD4 + T cells had no antitumor effects in the absence of CD8 + T cells and recognized the alloantigen cross-presented on tumor stroma. CD4 + T cells might also be effective in cancer patients when PD-1/PD-L1 blockade does not rescue intratumoral CD8 + T-cell function and tumors persist. Cancer Immunol Res; 5(2); 127-36. ©2017 AACR. (©2017 American Association for Cancer Research.)
Databáze:	MEDLINE
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