title: Molecular Programming of Tumor-Infiltrating CD8+ T Cells and IL15 Resistance.
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.
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, California.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Doedens
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, California. Department of Surgery, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Rubinstein
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, California.
authors.forename: Emilie T
authors.initials: ET
authors.lastname: Gross
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, California.
authors.forename: J Adam
authors.initials: JA
authors.lastname: Best
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: David H
authors.initials: DH
authors.lastname: Craig
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Megan K
authors.initials: MK
authors.lastname: Baker
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: David J
authors.initials: DJ
authors.lastname: Cole
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, California.
authors.forename: Jack D
authors.initials: JD
authors.lastname: Bui
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, California. agoldrath@ucsd.edu.
authors.forename: Ananda W
authors.initials: AW
authors.lastname: Goldrath
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D007155:Immunologic Factors / Q000378:metabolism / Q000494:pharmacology; D007156:Immunologic Memory; D019409:Interleukin-15 / Q000378:metabolism* / Q000494:pharmacology; D053720:Interleukin-15 Receptor alpha Subunit / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D047368:Tumor Burden
chemical_list: D016207:Cytokines; D007155:Immunologic Factors; D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit