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

Abstract

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 TGFβ 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 antibodies neutralizing IL23 in suppressing experimental lung metastases. The antimetastatic activity of anti-IL23R was dependent on NK cells and IFNγ 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 IFNγ-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. .

Decoding IL-23 Signaling Cascade for New Therapeutic Opportunities

“…For example, IL-23p19-deficient mice are resistant to tumor formation in a cutaneous chemical carcinogenesis model [221,222] and in colorectal cancer mouse models [223]. IL-23 has pro-tumor function in intestinal adenomas [224], lung metastases [225], and prostate cancer [226]. There is also evidence that IL-23 has a role in Alzheimer´s disease, as amyloidosis-prone APPPS1 mice lacking IL-23 and IL-12 have a decreased in amyloid-β plaque burden, and the administration of p40 neutralizing antibodies reduced the pathology [227].…”

Lethal-7-related polymorphisms are associated with susceptibility to and prognosis of gastric cancer

“…Interleukin-23 receptor (IL23R), a crucial subunit of the IL-23 receptor complex, is involved in innate and adaptive immune processes by interacting with IL-23, which plays a crucial role in many human diseases including autoimmune diseases and tumors[17,18]. Because IL23R presents tumor-promoting effects, knockdown of IL23R restricts tumor growth and decreases cancer metastasis[17,18].…”

“…Interleukin-23 receptor (IL23R), a crucial subunit of the IL-23 receptor complex, is involved in innate and adaptive immune processes by interacting with IL-23, which plays a crucial role in many human diseases including autoimmune diseases and tumors[17,18]. Because IL23R presents tumor-promoting effects, knockdown of IL23R restricts tumor growth and decreases cancer metastasis[17,18]. The rs10889677 polymorphism, located in the 3’-UTR of the IL23R gene, has been reported to be associated with cancer risk, including the risk of breast cancer[19], esophageal cancer[20], bladder cancer[21], ovarian cancer[22], oral cancer[23], and GC[24,25].…”

Targeting Myeloid-Derived Suppressor Cells in Cancer Immunotherapy

“…IL-23 produced by myeloid cells can effectively inhibit NK cells. After blocking IL-23R, the proportion of NK cells expressing IFNγ increased significantly [46]. Secreted IL-6 inhibits the proliferation and activation of NK cells.…”