Abstract
Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract, strongly associated with an increased risk of colorectal cancer development. Parasitic infections caused by helminths have been shown to modulate the host’s immune response by releasing immunomodulatory molecules and inducing regulatory T cells (Tregs). This immunosuppressive state provoked in the host has been considered as a novel and promising approach to treat IBD patients and alleviate acute intestinal inflammation. On the contrary, specific parasite infections are well known to be directly linked to carcinogenesis. Whether a helminth infection interferes with the development of colitis-associated colon cancer (CAC) is not yet known. In the present study, we demonstrate that the treatment of mice with the intestinal helminth Heligmosomoides polygyrus at the onset of tumor progression in a mouse model of CAC does not alter tumor growth and distribution. In contrast, H. polygyrus infection in the early inflammatory phase of CAC strengthens the inflammatory response and significantly boosts tumor development. Here, H. polygyrus infection was accompanied by long-lasting alterations in the colonic immune cell compartment, with reduced frequencies of colonic CD8+ effector T cells. Moreover, H. polygyrus infection in the course of dextran sulfate sodium (DSS) mediated colitis significantly exacerbates intestinal inflammation by amplifying the release of colonic IL-6 and CXCL1. Thus, our findings indicate that the therapeutic application of helminths during CAC might have tumor-promoting effects and therefore should be well-considered.
Highlights
A close relationship between inflammation and tumor development has been described for numerous human cancers over the last years [1]
Helminth parasites were tested for treating inflammatory bowel diseases (IBD) patients, resulting in clinical amelioration of the disease due to the induction of an immunosuppressive microenvironment
Some infection–related cancers can be attributed to helminth infection, probably due to the generation of a microenvironment that might be conductive to the initiation and development of cancer
Summary
A close relationship between inflammation and tumor development has been described for numerous human cancers over the last years [1]. The pathology of IBD is thought to be caused by either genetic susceptibility, environmental influences, infectious microbes, or dysregulated intestinal immune responses. While studying mouse models of intestinal inflammation, regulatory T cells (Tregs) were shown to play a critical role in maintaining mucosal homoeostasis. As they exert a variety of suppressive functions Tregs are able to prevent aberrant activation of intestinal immune responses [4]. In the murine model of colitisassociated colon cancer (CAC), CD4+ Foxp3+ Tregs are crucial for the control of the inflammatory process. During tumor progression, highly activated Tregs accumulate within colonic tumors and suppress CD8+ T cell antitumor responses effectively [5]
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