Molecular Programming of Tumor-Infiltrating CD8+ T Cells and IL15 Resistance.

Autor:	Doedens AL; Division of Biological Sciences, University of California, San Diego, La Jolla, California., Rubinstein MP; Division of Biological Sciences, University of California, San Diego, La Jolla, California. Department of Surgery, Medical University of South Carolina, Charleston, South Carolina., Gross ET; Department of Pathology, University of California, San Diego, La Jolla, California., Best JA; Division of Biological Sciences, University of California, San Diego, La Jolla, California., Craig DH; Department of Surgery, Medical University of South Carolina, Charleston, South Carolina., Baker MK; Department of Surgery, Medical University of South Carolina, Charleston, South Carolina., Cole DJ; Department of Surgery, Medical University of South Carolina, Charleston, South Carolina., Bui JD; Department of Pathology, University of California, San Diego, La Jolla, California., Goldrath AW; Division of Biological Sciences, University of California, San Diego, La Jolla, California. agoldrath@ucsd.edu.
Jazyk:	angličtina
Zdroj:	Cancer immunology research [Cancer Immunol Res] 2016 Sep 02; Vol. 4 (9), pp. 799-811. Date of Electronic Publication: 2016 Aug 02.
DOI:	10.1158/2326-6066.CIR-15-0178
Abstrakt:	Despite clinical potential and recent advances, durable immunotherapeutic ablation of solid tumors is not routinely achieved. IL15 expands natural killer cell (NK), natural killer T cell (NKT) and CD8(+) T-cell numbers and engages the cytotoxic program, and thus is under evaluation for potentiation of cancer immunotherapy. We found that short-term therapy with IL15 bound to soluble IL15 receptor α-Fc (IL15cx; a form of IL15 with increased half-life and activity) was ineffective in the treatment of autochthonous PyMT murine mammary tumors, despite abundant CD8(+) T-cell infiltration. Probing of this poor responsiveness revealed that IL15cx only weakly activated intratumoral CD8(+) T cells, even though cells in the lung and spleen were activated and dramatically expanded. Tumor-infiltrating CD8(+) T cells exhibited cell-extrinsic and cell-intrinsic resistance to IL15. Our data showed that in the case of persistent viral or tumor antigen, single-agent systemic IL15cx treatment primarily expanded antigen-irrelevant or extratumoral CD8(+) T cells. We identified exhaustion, tissue-resident memory, and tumor-specific molecules expressed in tumor-infiltrating CD8(+) T cells, which may allow therapeutic targeting or programming of specific subsets to evade loss of function and cytokine resistance, and, in turn, increase the efficacy of IL2/15 adjuvant cytokine therapy. Cancer Immunol Res; 4(9); 799-811. ©2016 AACR. (©2016 American Association for Cancer Research.)
Databáze:	MEDLINE
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