1. Host IL11 Signaling Suppresses CD4+ T cell–Mediated Antitumor Responses to Colon Cancer in Mice
- Author
-
Lokman Pang, David Baloyan, Shoukat Afshar-Sterle, David Chisanga, Louis Boon, Pathum Thilakasiri, Mariah G. Alorro, Matthias Ernst, Jennifer Huynh, Wei Shi, David S. Williams, Moritz F. Eissmann, Megan O'Brien, Frederick Masson, Ashwini L. Chand, Adam C. Parslow, Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Heidelberg, Victoria, Australia., Polpharma Biologics, Utrecht, the Netherlands, and Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, CNRS, INSERM, UPS, Toulouse, France. (Infinity)
- Subjects
0301 basic medicine ,Cancer Research ,Tumor microenvironment ,Colorectal cancer ,[SDV]Life Sciences [q-bio] ,Immunology ,Cancer ,Biology ,medicine.disease ,Glycoprotein 130 ,3. Good health ,Proinflammatory cytokine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,medicine ,Tumor necrosis factor alpha ,Bone marrow ,ComputingMilieux_MISCELLANEOUS - 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.
- Published
- 2021
- Full Text
- View/download PDF