Manipulation of IL-2 signals by IL-2/antibody complex and CD25 blockade improves tumor immunity, reprograms regulatory T cells, and augments CD8+ central memory in an ovarian cancer model

Abstract

Abstract We used a defined IL-2/αIL-2 complex that directs IL-2 to stimulate only intermediate-affinity IL-2 receptor (CD122/132) to promote tumor rejection and avoid regulatory T cell (Treg) expansion. However, it is unknown if IL-2/αIL-2 alters Treg function, as Tregs also express CD122/132. After challenge with ID8agg ovarian cancer (OC) cells, IL-2/αIL-2 greatly reduced tumor burden, and increased IFN-γ, TNF-α, CD44, and CD25 in CD4+ non-Tregs and CD8+ T cells, as expected. IL-2/αIL-2 was clinically effective, yet it lowered the ascites CD8+/FoxP3+ Treg ratio and increased per cell FoxP3 levels in Tregs, suggesting a change in Treg function. IL-2/αIL-2 decreased the ratio of CD62L+ central Tregs to CD44+ effector Tregs in ID8agg ascites, indicating modulation of Treg differentiation. Surprisingly, ascites Tregs produced IFN-γ, IL-2, and TNF-α in control-treated OC mice, which was abolished by IL-2/αIL-2, suggesting further alteration of Treg differentiation and function. CD25 (high-affinity IL-2 receptor subunit) expression on Tregs was reduced by IL-2/αIL-2, which could lower Treg IL-2 sequestration and increase IL-2 available to antitumor T cells. CD25 blockade with αCD25 during IL-2/αIL-2 treatment reduced clinical efficacy but greatly increased central memory (CM; CD62L+CD44+) CD8+ T cells in blood and mesenteric (tumor-draining) lymph nodes. Thus, reduction of tumor burden by IL-2/αIL-2 is associated with reprogramming of Treg differentiation and function in an OC model. CD25 blockade after IL-2/αIL-2 could improve response durability by boosting CM CD8+ formation. These data demonstrate novel effects of IL-2-modulating drugs on Tregs and CD8+ memory and will aid development of more effective anticancer immunotherapy.