期刊
CANCER IMMUNOLOGY RESEARCH
卷 4, 期 12, 页码 1016-1026出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-16-0159
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Interleukin-2 (IL2) was among the earliest reagents used for cancer immunotherapy due to its ability to support the survival and function of tumor-reactive T cells. However, treatment with IL2 is accompanied by off-target toxicity and low response rates in patients. In mouse models, these issues are largely overcome when IL2 is administered as a cytokine/antibody complex (IL2c). The complex has a longer serum half-life and can be designed for preferential cytokine delivery to specific cells of interest. Early studies showed IL2c could boost antitumor immunity in mice by activating tumor-reactive CD8(+) T cells. But such functional T cells are often limited in the tumor microenvironment, where instead unresponsive tolerant T cells are eventually eliminated by apoptosis, representing a major obstacle to the success of cancer immunotherapy. We found that IL2c treatment rescued tumor-specific CD8(+) T cells from a state of established tolerance, providing effective immunotherapy in tumor-bearing mice. Expression of the transcription factor T-bet was necessary to drive intratumoral IFN gamma production and effector activity by T cells rescued with IL2c. Furthermore, IL2c promoted T-bet expression in human CD4(+) and CD8(+) T cells in humanized tumor-bearing mice, but also increased the frequency of Foxp3(+) regulatory T cells. Our study reveals a novel role for IL2c as a powerful immunotherapeutic reagent capable of reversing tolerance in tumor-reactive T cells, and provides the first evidence that IL2c influences human T cells in vivo, highlighting the translational potential to modulate human antitumor immune responses. (C) 2016 AACR.
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