American Association for Cancer Research
23266066cir160159-sup-168848_1_supp_3689462_wwhwwp.pptx (59.19 kB)

Supplementary Figure S2 from Rescue of Tolerant CD8+ T Cells during Cancer Immunotherapy with IL2:Antibody Complexes

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posted on 2023-04-03, 23:00 authored by Lauryn E. Klevorn, Melissa M. Berrien-Elliott, Jinyun Yuan, Lindsey M. Kuehm, Gregory D. Felock, Sean A. Crowe, Ryan M. Teague

Tbx21-/- T cells produce less IFNgamma after IL-2c treatment compared to WT



Cancer Research Institute CLIP award

Siteman Cancer Center and The Foundation for Barnes-Jewish Hospital

Saint Louis University Presidential Graduate Fellowship



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 IFNγ 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. Cancer Immunol Res; 4(12); 1016–26. ©2016 AACR.