Interleukin-2 signals converge in a lymphoid-dendritic cell pathway that promotes anticancer immunity.

Abstract

Tumor-infiltrating dendritic cells (DCs) correlate with effective anticancer immunity and improved responsiveness to anti-PD-1 checkpoint immunotherapy. However, the drivers of DC expansion and intratumoral accumulation are ill-defined. We found that interleukin-2 (IL-2) stimulated DC formation through innate and adaptive lymphoid cells in mice and humans, and this increase in DCs improved anticancer immunity. Administration of IL-2 to humans within a clinical trial and of IL-2 receptor (IL-2R)-biased IL-2 to mice resulted in pronounced expansion of type 1 DCs, including migratory and cross-presenting subsets, and type 2 DCs, although neither DC precursors nor mature DCs had functional IL-2Rs. In mechanistic studies, IL-2 signals stimulated innate lymphoid cells, natural killer cells, and T cells to synthesize the cytokines FLT3L, CSF-2, and TNF. These cytokines redundantly caused DC expansion and activation, which resulted in improved antigen processing and correlated with favorable anticancer responses in mice and patients. Thus, IL-2 immunotherapy-mediated stimulation of DCs contributes to anticancer immunity by rendering tumors more immunogenic.