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

Juming Yan,Xian-Yang Li,Michele W.L Teng,Dipti Vijayan,Kazuyoshi Takeda,Jing Liu,Daniel J Cua,Heidi Harjunpää,Mark J Smyth,Stacey Allen

doi:10.1158/2326-6066.cir-18-0011

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. Cancer Immunol Res; 6(8); 978-87. ©2018 AACR.

Highlights

Tumor-induced immune suppression, used by tumors to evade immune destruction [1], can be mediated through lymphoid and myeloid cells
The number of B16F10 lung metastases as well as LWT1 and RM-1 experimental lung metastases was significantly decreased in IL23R–/– mice compared with IL23p19–/– mice (Fig. 1A–C)
We found that targeting IL23R compared with IL23p19 was more effective in suppressing three different experimental lung metastasis models

Summary

Introduction

Tumor-induced immune suppression, used by tumors to evade immune destruction [1], can be mediated through lymphoid and myeloid cells. T-cell immune checkpoint blockade alone, or in combination with other antitumor approaches, has demonstrated clinical efficacy in many cancer types [2], many patients do not respond to these current therapies. As tumors can be heterogeneous with respect to lymphoid and myeloid infiltrates, there is interest in targeting immunosuppressive pathways mediated by myeloid cells in the tumor microenvironment (TME). Myeloid cells in the TME can be abundant and include tumorassociated macrophages and myeloid-derived suppressor cells (MDSC). Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

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