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

• Published in: Cancer immunology research 2016-09, Vol.4 (9), p.799-811
• Main Authors: Doedens, Andrew L, Rubinstein, Mark P, Gross, Emilie T, Best, J Adam, Craig, David H, Baker, Megan K, Cole, David J, Bui, Jack D, Goldrath, Ananda W
• Format: Article
• Language: English
• Subjects: Animals; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cytokines - metabolism; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Immunologic Factors - metabolism; Immunologic Factors - pharmacology; Immunologic Memory; Interleukin-15 - metabolism; Interleukin-15 - pharmacology; Interleukin-15 Receptor alpha Subunit - metabolism; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Mice; Mice, Transgenic; Neoplasms - drug therapy; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - pathology; Tumor Burden
• ISSN: 2326-6066; 2326-6074
• DOI: 10.1158/2326-6066.CIR-15-0178

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.