Host IL-11 signaling suppresses CD4+ T cell-mediated anti-tumor responses to colon cancer in mice.

Abstract

Interleukin-11 (IL-11) is a member of the IL-6 family of cytokines and signals through its cognate receptor subunits, IL11RA and glycoprotein 130 (GP130) to elicit biological responses via the JAK/STAT signaling pathway. IL-11 contributes to cancer progression by promoting the survival and proliferation of cancer cells, but the potential immunomodulatory properties of IL-11 signaling during tumor development have thus far remained unexplored. Here, we have characterized a role for IL-11 in regulating CD4+ T cell-mediated anti-tumor responses. Absence of IL-11 signaling impaired tumor growth in a sporadic mouse model of colon cancer and syngeneic allograft models of colon cancer. Adoptive bone marrow transfer experiments and in vivo depletion studies demonstrated that the tumor-promoting activity of IL-11 was mediated through its suppressive effect on host CD4+ T cells in the tumor microenvironment. Indeed, when compared to Il11ra-proficient CD4+ T cells associated with MC38 tumors, their Il11ra-deficient counterparts displayed elevated expression of mRNA encoding the anti-tumor mediators IFNγ and TNFα. Likewise, IL-11 potently suppressed the production of pro-inflammatory cytokines (IFNγ, TNFα, IL-6, and IL12p70) by CD4+ T cells in vitro, which we corroborated by RNAscope analysis of human colorectal cancers, where IL11RAhigh tumors showed less IFNG and CD4 expression than IL11RAlow tumors. Therefore, our results ascribe for a tumor-cell extrinsic immunomodulatory role for IL-11 during tumor development that is amenable to anti-cytokine based clinical management of colon cancer.