Enhanced STAT5a activation opposes Tox and rewires exhausted CD8 T cells towards a hybrid durable effector-like state during chronic stimulation [ATAC-postChallenge]

Here, we discovered a reciprocal antagonism between Stat5a and Tox in TEX cells. Stat5a antagonized the Tox-mediated exhaustion program to achieve a durable and protective hybrid effector/NK-like differentiation state in settings that typically drive exhaustion. Stat5 also drove TEX progenitors to differentiate into the effector-like TEXint subset, a key developmental step for PD-1 blockade responsiveness. Therapeutic enhancement of Stat5 activity in TEX cells using an orthogonal IL-2/IL2Rb pair system fostered TEXint cell accumulation and synergized with PD-L1 blockade. Finally, targeted delivery of Stat5-signals in TEX progenitors achieved partial epigenetic rewiring of these cells towards the effector/memory lineage and revived polyfunctionality. Together, these data highlight therapeutic opportunities of targeting Stat5 to antagonize the Tox-dependent epigenetic programming of TEX and provoke a hybrid program that exploits effector biology and durability for optimal therapeutic potential ATAC-postChallenge, LCMV Armstrong