Huynh Jennifer, Baloyan David, Chisanga David, Shi Wei, O'Brien Megan, Afshar-Sterle Shoukat, Alorro Mariah, Pang Lokman, Williams David S, Parslow Adam C, Thilakasiri Pathum, Eissmann Moritz F, Boon Louis, Masson Frederick, Chand Ashwini L, Ernst Matthias
Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Heidelberg, Victoria, Australia.
Department of Pathology, Austin Health, Heidelberg, Victoria, Australia.
Cancer Immunol Res. 2021 Jul;9(7):735-747. doi: 10.1158/2326-6066.CIR-19-1023. Epub 2021 Apr 27.
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 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 -proficient CD4 T cells associated with MC38 tumors, their -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 , which we corroborated by RNAscope analysis of human colorectal cancers, where IL11RA tumors showed less and expression than IL11RA 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..
白细胞介素11（IL11）是细胞因子IL6家族的成员，通过其同源受体亚基IL11RA和糖蛋白130（GP130）发出信号，经由JAK/STAT信号通路引发生物学反应。IL11通过促进癌细胞的存活和增殖促进癌症进展，但迄今为止，IL11信号在肿瘤发生过程中的潜在免疫调节特性仍未得到探索。在此，我们阐述了IL11在调节CD4 T细胞介导的抗肿瘤反应中的作用。在散发性结肠癌小鼠模型和结肠癌同基因移植模型中，IL11信号缺失会损害肿瘤生长。过继性骨髓移植实验和清除研究表明，IL11的促肿瘤活性是通过其对肿瘤微环境中宿主CD4 T细胞的抑制作用介导的。实际上，与MC38肿瘤相关的IL11功能正常的CD4 T细胞相比，其IL11缺陷的对应细胞显示出编码抗肿瘤介质IFNγ和TNFα的mRNA表达升高。同样，IL11强烈抑制CD4 T细胞产生促炎细胞因子（IFNγ、TNFα、IL6和IL12p70），我们通过对人类结直肠癌的RNAscope分析证实了这一点，其中IL11RA高表达的肿瘤比IL11RA低表达的肿瘤显示出更少的IFNγ和TNFα表达。因此，我们的结果表明，IL11在结肠癌发生过程中具有肿瘤细胞外源性免疫调节作用，这可能适用于基于抗细胞因子的治疗。
