Host IL11 Signaling Suppresses CD4+ T cell-Mediated Antitumor Responses to Colon Cancer in Mice

Y IL11 is a member of the IL6 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. IL11 contributes to cancer progression by promoting the survival and proliferation of cancer cells, but the potential immunomodulatory properties of IL11 signaling during tumor development have thus far remained unexplored. Here, we have characterized a role for IL11 in regulating CD4+ T cell-mediated antitumor responses. Absence of IL11 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 IL11 was mediated through its suppressive effect on host CD4(+) T cells in the tumor microenvironment. Indeed, when compared with Il11r alpha- proficient CD4(+) T cells associated with MC38 tumors, their Il11r alpha- deficient counterparts displayed elevated expression of mRNA encoding the antitumor mediators IFN gamma and TNF alpha. Likewise, IL11 potently suppressed the production of proinflammatory cytokines (IFN gamma, TNF alpha, IL6, and IL12p70) by CD4(+) T cells in vitro, which we corroborated by RNAscope analysis of human colorectal cancers, where IL11RA(high) tumors showed less IFNG and CD4 expression than IL11RA(low) tumors. Therefore, our results ascribe a tumor cell-extrinsic immunomodulatory role to IL11 during colon cancer development that could be amenable to an anticytokinebased therapy.

Automated summary

IL11 is a member of the IL6 family of cytokines, and plays a role in regulating CD4+ T cell-mediated antitumor responses by suppressing the activity of host CD4(+) T cells in the tumor microenvironment. This suggests a potential immunomodulatory role for IL11 in colon cancer development that could be targeted for anticytokine-based therapy.