1. Molecular Programming of Tumor-Infiltrating CD8+ T Cells and IL15 Resistance
- Author
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Doedens, Andrew L, Rubinstein, Mark P, Gross, Emilie T, Best, J Adam, Craig, David H, Baker, Megan K, Cole, David J, Bui, Jack D, and Goldrath, Ananda W
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Cancer ,Immunization ,Vaccine Related ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Animals ,CD8-Positive T-Lymphocytes ,Cytokines ,Drug Resistance ,Neoplasm ,Female ,Gene Expression Regulation ,Neoplastic ,Immunologic Factors ,Immunologic Memory ,Interleukin-15 ,Interleukin-15 Receptor alpha Subunit ,Lymphocytes ,Tumor-Infiltrating ,Mice ,Mice ,Transgenic ,Neoplasms ,Tumor Burden ,Pharmacology and Pharmaceutical Sciences ,Oncology and carcinogenesis - Abstract
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.
- Published
- 2016