IL-2Ra-biased, but not ß?-biased, agonist reprograms tumor immune landscape and synergize with aPD-1 therapy

We investigated whether exogenous supplies of different IL-2R agonists (IL-2wt, IL-2na or IL-2a-bias) at the concentration of 3 mg/g body weight could rescue the transcriptional signatures of dysfunctional T cells in large tumors, or allow them to regain sensitivity to aPD-1 antibody. Remarkably, after transient stimulation by IL-2wt, large tumors fully restored the effector/activation signatures observed in small tumors, such as upregulation of effector genes (Gzma, Gzmb, Gzmk and Ifng), T cell activation/exhaustion genes (Ctla4, Pdcd1, Lag3 and Havcr2), inflammatory cytokine/cytokine receptors (Il2ra, Il2rb, Il2rg and Il21r), and chemokines (Cxcl9, Cxcl10 and Ccl19) (Fig.7d). Surprisingly, although IL-2a-bias had >10-fold weaker in vitro activity than IL-2wt, and could only activate the small fraction of CD25-upregulated CD8+Teff cells, the transcriptional profiles were indistinguishable between IL-2wt and IL-2a-bias treated large tumors. In stark contrast, IL-2na treatment showed no meaningful transcriptional changes in large tumors compared to untreated control. These results once again demonstrate the critical role of CD25 in transmitting IL-2 signaling to reprogram the tumor immune microenvironment.