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Published on: June 12, 2021
Molecular Programming of Tumor-Infiltrating CD8+ T Cells and IL15 Resistance
Andrew L Doedens1, Mark P Rubinstein2, Emilie T Gross3
1Division of Biological Sciences, University of California, San Diego, La Jolla, California.
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.
Insights
Interleukin-15 (IL15) therapy showed limited effectiveness against solid tumors. Tumor-infiltrating CD8(+) T cells resisted IL15, suggesting new strategies are needed for effective cancer immunotherapy.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Durable immunotherapeutic ablation of solid tumors remains a challenge.
- Interleukin-15 (IL15) expands cytotoxic immune cells and is being evaluated for cancer immunotherapy.
- IL15 receptor alpha-Fc (IL15cx) is a modified form of IL15 with enhanced activity.
Purpose of the Study:
- To evaluate the efficacy of IL15cx in treating autochthonous PyMT murine mammary tumors.
- To investigate the mechanisms behind the poor responsiveness of tumors to IL15cx therapy.
- To identify strategies for improving IL15/IL2-based cancer immunotherapy.
Main Methods:
- Treatment of PyMT murine mammary tumors with IL15cx.
- Analysis of CD8(+) T-cell activation, expansion, and phenotype within tumors, lungs, and spleen.
- Identification of molecular markers on tumor-infiltrating CD8(+) T cells.
Main Results:
- Short-term IL15cx therapy was ineffective against established mammary tumors.
- Intratumoral CD8(+) T cells showed weak activation and resistance to IL15cx, unlike cells in the spleen and lungs.
- Tumor-infiltrating CD8(+) T cells exhibited exhaustion and expressed tissue-resident memory markers, indicating resistance to IL15.
- Systemic IL15cx treatment expanded antigen-irrelevant or extratumoral CD8(+) T cells.
Conclusions:
- Systemic IL15cx monotherapy is insufficient for treating solid tumors due to CD8(+) T-cell resistance.
- Identifying and targeting specific molecular markers on tumor-infiltrating CD8(+) T cells could overcome resistance.
- Targeting these subsets may enhance the efficacy of IL2/15-based cytokine therapies for cancer treatment.
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