Rescue of tolerant CD8⁺ T cells during cancer immunotherapy with IL2: Antibody complexes

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 IFNg 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.