Intestinal helminth infection drives carcinogenesis in colitis-associated colon cancer

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.

Author summary

Evidence from epidemiological studies indicates an inverse correlation between the incidence of certain immune-mediated diseases, including inflammatory bowel diseases, and exposure to helminths. As a consequence, helminth parasites were tested for treating IBD patients, resulting in clinical amelioration of the disease due to the induction of an immunosuppressive microenvironment. However, 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. In the present study, we aimed to unravel the apparently controversial function of helminths in a mouse model of colitis-associated colon cancer. We show that helminth infection in the onset of colitis and colitis-associated colon cancer does not ameliorate colonic inflammation but activates intestinal immune cells that further facilitate tumor development. Therefore, a better understanding of mechanisms by which helminths modulate host immune responses in the gut should be defined precisely before application of helminths in autoimmune diseases like IBD.