Experimental Lung Metastases in Mice Are More Effectively Inhibited by Blockade of IL23R than IL23

Tumor-induced immunosuppression is mediated through various mechanisms including engagement of immune checkpoint receptors on effector cells, function of immunoregulatory cells such as regulatory T cells and myeloid-derived suppressor cells, and deployment of immunosuppressive cytokines such as TGF beta and IL10. IL23 is a cytokine that negatively affects antitumor immunity. In this study, we investigated whether IL23-deficient (IL23p19(-/-)) and IL23R-deficient (IL23R(-/-)) mice phenocopied each other, with respect to their tumor control. We found that IL23R(-/-) mice had significantly fewer lung metastases compared with IL23p19(-/-) mice across three different experimental lung metastasis models (B16F10, LWT1, and RM-1). Similarly, IL23R blocking antibodies were more effective than anti-bodies neutralizing IL23 in suppressing experimental lung metastases. The antimetastatic activity of anti-IL23R was dependent on NK cells and IFN gamma but independent of CD8(+) T cells, CD4(+) T cells, activating Fc receptors, and IL12. Furthermore, our data suggest this increased antitumor efficacy was due to an increase in the proportion of IFN gamma-producing NK cells in the lungs of B16F10 tumor-bearing mice. Anti-IL23R, but not anti-IL23p19, partially suppressed lung metastases in tumor-bearing mice neutralized for IL12p40. Collectively, our data imply that IL23R has tumor-promoting effects that are partially independent of IL23p19. Blocking IL23R may be more effective than neutralizing IL23 in the suppression of tumor metastases. (C) 2018 AACR.