IL-7R licenses a population of epigenetically poised memory CD8+T cells with superior antitumor efficacy that are critical for melanoma memory

Recurrence of advanced melanoma after therapy is a major risk factor for reduced sur-vival, and treatment options are limited. Antitumor immune memory plays a critical role in preventing melanoma recurrence and memory T cells could be a potent cell -based therapy, but the identity, and functional properties of the required immune cells are incompletely understood. Here, we show that an IL-7Rhi tumor-specific CD8(+) popula-tion is critical for antitumor memory and can be epigenetically augmented to drive pow-erful antitumor immune responses. Using a model of functional antimelanoma memory, we found that high IL-7R expression selectively marks a CD8(+) population in lymphoid organs that plays critical roles in maintaining tumor remission after immunotherapy or surgical resection. This population has intrinsic cytotoxic activity, lacks markers of exhaustion and has superior antitumor efficacy. IL-7Rhi cells have a functionally poised epigenetic landscape regulated by DNA methylation, which can be augmented by hypo-methylating agents to confer improved survival and complete melanoma clearance in naive mice. Importantly, greater than 95% of tumor-specific T cells in draining lymph nodes after therapy express high levels of IL-7R. This overlap between IL-7Rhi and antigen-specific T cells allows for enrichment of a potent functional CD8(+) population without determining antigen-specificity, which we demonstrate in a melanoma model without a known antigen. We identify that IL-7R expression in human melanoma is an independent prognostic factor of improved survival. These findings advance our basic understanding of antitumor memory and suggest a cell -based therapy using high IL-7R expression to enrich for a lymph node population with superior antitumor activity that can be augmented by hypomethylating agents. Significance Treatment options for patients with recurrent melanoma are limited and understanding antitumor memory is critical to prevent recurrence and develop improved therapies. Previous studies found that adoptively transferring antigen-specific T cells with memory traits provides improved clinical benefit, suggesting that antitumor memory T cells could be the ideal candidate for cell -based therapies. However, this population and its markers remain elusive. We analyzed tumor-specific T cells using single -cell approaches in a model of antimelanoma memory. Our results identify a CD8(+) population selectively marked by IL-7R expression that drives antitumor memory and can be used as a potent therapy for melanoma. The antitumor function of this population can be epigenetically augmented to develop powerful adoptive cell therapies that could improve melanoma survival.