American Association for Cancer Research
23266066cir150178-sup-152867_1_supp_3533784_t8kbxy.pdf (1.95 MB)

Supplemental Table 3 from Molecular Programming of Tumor-Infiltrating CD8+ T Cells and IL15 Resistance

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journal contribution
posted on 2023-04-03, 23:04 authored by Andrew L. Doedens, Mark P. Rubinstein, Emilie T. Gross, J. Adam Best, David H. Craig, Megan K. Baker, David J. Cole, Jack D. Bui, Ananda W. Goldrath

PyMT tumor CD8+ versus day 5 effector OT-I gene expression and fold change.



UCSD Cancer Biology

Hartwell Foundation Collaboration



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.

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