IL-2Rα-biased agonist enhances antitumor immunity by invigorating tumor-infiltrating CD25+CD8+ T cells

Abstract

To avoid regulatory T cell promotion and vascular toxicity, the interleukin-2 receptor-β/interleukin-2 receptor-γ (IL-2Rβγ)-biased approach is used by most IL-2 analogs in immuno-oncology. However, recent clinical disappointments in these IL-2 agonists have questioned this strategy. Here we show that both wild-type (IL-2^wt) and IL-2Rβγ-attenuated (IL-2^α-bias) agonists that preserve IL-2Rα (CD25) activities can effectively expand tumor-specific CD8⁺ T cells (TSTs) and exhibit better antitumor efficacy and safety than the 'non-α' counterpart (IL-2^nα). Mechanistically, TSTs coexpress elevated CD25 and PD-1 and are more susceptible to stimulation by IL-2Rα-proficient agonists. Moreover, the antitumor efficacy of anti-PD-1 depends on activation of PD-1⁺CD25⁺ TSTs through autocrine IL-2-CD25 signaling. In individuals with cancer, a low IL-2 signature correlates with non-responsiveness to anti-PD-1 treatment. In mouse models, IL-2^α-bias, but not IL-2^nα, restores the IL-2 signature and synergizes with anti-PD-1 to eradicate large established tumors. These findings underscore the indispensable function of CD25 in IL-2-based immunotherapy and provide rationales for evaluating IL-2Rα-biased agonists in individuals with cancer.