An engineered IL-2 partial agonist promotes CD8+ T cell stemness and anti-tumor efficacy

Abstract

Abstract Adoptive cell transfer of antigen specific T cells represents a major advance in cancer immunotherapy, with robust clinical outcomes in a subset of patients. To achieve effective responses, both the number of transferred T cells and their cell differentiation state are critical determinants. T cells can be expanded with T cell receptor (TCR)-mediated stimulation and IL-2 but this can also lead to T cell differentiation into effector T cells, resulting in diminished therapeutic efficacy, whereas maintenance of a more stem-like prior to adoptive transfer is beneficial. Here, we show that an engineered IL-2 partial agonist generated on the super-IL-2 background promoted T-cell expansion without driving terminal differentiation. The partial agonist exhibited altered signaling and mediated distinctive downstream transcriptional, epigenetic, and metabolic programs. Moreover, it sustained expression of transcription factor TCF-1 (T cell transcription factor 1) and promoted mitochondrial fitness, facilitating the maintenance of a stem cell-like state. Accordingly, TCR transgenic and CAR-modified CD8+ T cells expanded with this engineered molecule displayed robust anti-tumor activity in vivo in established models of melanoma and acute lymphoblastic leukemia. Thus, tempering cytokine signaling with the IL-2 partial agonist provides a strategy for enhancing therapeutic efficacy by limiting exhaustion while preserving stemness. Moreover, our findings demonstrate the distinctive power of generation cytokine partial agonists with distinctive activities.