IL-10 secretion by CD8 T cells orchestrates early NK cell recruitment and antitumor immunity after anti-VEGFR-2/PD-1 therapy

BACKGROUND: The combination of antiangiogenic therapy with immune checkpoint blockade has demonstrated significant clinical benefits in various cancers, however, the precise mechanisms of action on the immune system are not fully understood. In particular, the early intratumoral immune responses induced by angiogenesis inhibition remain unclear. METHODS: Using preclinical models of colorectal cancer, we examined the immune changes elicited by combined vascular endothelial growth factor receptor-2 (VEGFR-2) and programmed cell death protein-1 (PD-1) blockade. RESULTS: Our findings reveal that CD8 T cells respond directly and early to VEGFR-2 inhibition, preceding the acquisition of overt cytotoxic function. Shortly after treatment, intratumoral CD8 T cells expanded and produced interleukin-10 (IL-10). Unexpectedly, this CD8 T cell-derived IL-10 promoted the recruitment of natural killer (NK) cells into tumors. Recruited NK cells subsequently gained effector activity and produced granulocyte-macrophage colony-stimulating factor, which supported macrophage maturation and the induction of CXCL11. This sequence of events enhanced secondary CD8 T-cell infiltration and sustained antitumor immune activity. Disruption of IL-10 signaling or NK-cell function eliminated the therapeutic benefit of combined VEGFR-2 and PD-1 blockade, whereas regulatory T-cell depletion further improved tumor control. CONCLUSIONS: Together, these findings identify an unanticipated role for CD8 T cell-derived IL-10 in coordinating early innate and adaptive immune responses following angiogenesis inhibition and define an immune program initiated by VEGFR-2 blockade that is required for therapeutic efficacy in two preclinical colorectal cancer models.