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

Abstract

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 Il11ra-proficient CD4+ T cells associated with MC38 tumors, their Il11ra-deficient counterparts displayed elevated expression of mRNA encoding the antitumor mediators IFNγ and TNFα. Likewise, IL11 potently suppressed the production of proinflammatory cytokines (IFNγ, TNFα, IL6, 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 a tumor cell–extrinsic immunomodulatory role to IL11 during colon cancer development that could be amenable to an anticytokine-based therapy. See related Spotlight by van der Burg, p. 724.

Tumor-specific T cells support chemokine-driven spatial organization of intratumoral immune microaggregates needed for long survival

“…A number of the upregulated DEGs (p<0.05) in HPV16 + IR − OPSCC compared with HPV16 + IR + OPSCC are associated with suppressive myeloid cells ( CCL20 , CXCL3 , CSF2 , TREM1 , and IL-1B ), 24 angiogenesis ( CXCL8 ), 25 transforming growth factor (TGF)-β pathway ( INHBA and BMP2 ), 26 and immune suppression ( IL-11 ). 27 The top upregulated DEGs in HPV16 + IR + compared with its IR − counterpart were BLK , reflecting B cells ( online supplemental figure 2C ), and the chemokines LTB and CXCL12 , which are involved in ectopic lymphoid structure development, required for the coordination of adaptive immune responses. 28 Interestingly, the well-known chemokines for T-cell attraction, CXCL9 , CXCL10 , and CXCL11 , did not differ.…”

“…Increased expression of the TGF-β superfamily members INHBA and BMP2 26 was also found in our transcriptomic analyses. The presence of these immune suppressive cells 52–54 and the increased expression of the immune suppressive cytokine IL-11 , known to suppress the attraction and functionality of tumor-reactive CD4 + T cells, 27 potentially explain why tumor-specific T cells were not detected in these tumors. It also provides a rational foundation for combinations of T cell-stimulating agents 6 55 56 with strategies focusing on the identified resistance mechanisms, for example, cotargeting M2-like macrophages, 57 TGF-β, 58 and/or angiogenesis.…”

STAT3 Signaling in Breast Cancer: Multicellular Actions and Therapeutic Potential

“…Although the relationship between TGFβ /IL-11 signaling was explored mainly in CAFs, the effects of IL-11 on mechanisms of immune evasion during cancer metastasis have not yet been demonstrated in any cancer context. Although, we have evaluated the role of IL-11 signaling on immune cell activity in primary tumors using CRC models to demonstrate a prominent role of IL-11 in mediating CD4 + T cell-dependent immune-evasion in the tumor microenvironment [ 97 ].…”

Structures of the interleukin 11 signalling complex reveal dynamics of gp130 extracellular domains and the inhibitory mechanism of a cytokine variant

“…Interleukin (IL-)11 is secreted by numerous immune cells including CD8+ T-cells, B-cells, macrophages, natural killer (NK) cells, γδT cells, and eosinophils, and has been implicated in the differentiation of B-cells, T-cells, and anti-tumour immune responses [1][2][3][4][5] . IL-11 is also produced by inflammatory fibroblasts and epithelial cells resulting in a coordinated wound response to enable the maintenance of mucosal barriers [6][7][8][9][10][11] .…”