Patients with inflammatory bowel disease (IBD) have increased incidence of colorectal cancer (CRC). IBD-associated cancer follows a well-characterized sequence of intestinal epithelial changes, in which genetic mutations and molecular aberrations play a key role. IBD-associated cancer develops against a background of chronic inflammation and pro-inflammatory immune cells, and their products contribute to cancer development and progression. In recent years, the effect of the immunosuppressive microenvironment in cancer development and progression has gained more attention, mainly because of the unprecedented anti-tumor effects of immune checkpoint inhibitors in selected groups of patients. Even though IBD-associated cancer develops in the background of chronic inflammation which is associated with activation of endogenous anti-inflammatory or suppressive mechanisms, the potential role of an immunosuppressive microenvironment in these cancers is largely unknown. In this review, we outline the role of the immune system in promoting cancer development in chronic inflammatory diseases such as IBD, with a specific focus on the anti-inflammatory mechanisms and suppressive immune cells that may play a role in IBD-associated tumorigenesis.

Stressed gut epithelium gets some relief: Immunoglobulin A (IgA) is the most abundantly expressed antibody isotype and can be found at various mucosal surfaces in the body, including the gastrointestinal (GI) tract. IgA is polyreactive and can coat and restrain both commensal bacteria and enteric pathogens. Grootjans et al. found that endoplasmic reticulum (ER) stress in the intestinal epithelial cells of mice induced the T cell– and microbiota-independent expansion of peritoneal B1b cells, which secrete IgA. Similarly, human subjects homozygous for a variant of an autophagy gene ( ATG16L1 ) known to cause ER stress showed increased numbers of GI IgA ⁺ cells compared with controls. Thus, epithelial ER stress serves as an advantageous “eustress” response that can functionally antagonize its well-characterized role in promoting inflammation. Science , this issue p. 993

Intelectin-1 (ITLN1) is a lectin secreted by intestinal epithelial cells (IECs) and upregulated in human ulcerative colitis (UC). We investigated how ITLN1 production is regulated in IECs and the biological effects of ITLN1 at the host–microbiota interface using mouse models. Our data show that ITLN1 upregulation in IECs from UC patients is a consequence of activating the unfolded protein response. Analysis of microbes coated by ITLN1 in vivo revealed a restricted subset of microorganisms, including the mucolytic bacterium Akkermansia muciniphila. Mice overexpressing intestinal ITLN1 exhibited decreased inner colonic mucus layer thickness and closer apposition of A. muciniphila to the epithelial cell surface, similar to alterations reported in UC. The changes in the inner mucus layer were microbiota and A. muciniphila dependent and associated with enhanced sensitivity to chemically induced and T cell–mediated colitis. We conclude that by determining the localization of a select group of bacteria to the mucus layer, ITLN1 modifies this critical barrier. Together, these findings may explain the impact of ITLN1 dysregulation on UC pathogenesis.

Despite advances in the medical management of ulcerative colitis (UC), a subgroup of patients does not respond to currently available therapies. A number of novel drugs are in late stages of clinic...

Although the number of therapeutic options for the treatment of inflammatory bowel disease (IBD) has increased in recent years, patients suffer from decreased quality of life due to non-response or loss of response to the currently available treatments. An increased understanding of the disease’s etiology could provide novel insights for treatment strategies in IBD. Lymphatic system components are generally linked to immune responses and presumably related to inflammatory diseases pathophysiology. This review aims to summarize findings on immune-mediated mechanisms in lymphoid tissues linked with IBD pathogenesis and (potential) novel treatments. Enhanced innate and adaptive immune responses were observed in mesenteric lymph nodes (MLNs) and other lymphoid structures, such as Peyer’s patches, in patients with IBD and in animal models. Furthermore, the phenomenon of lymphatic obstruction in the form of granulomas in MLNs and lymphatic vessels correlates with disease activity. There is also evidence that abnormalities in the lymphatic stromal components and lymph node microbiome are common in IBD and could be exploited therapeutically. Finally, novel agents targeting lymphocyte trafficking have been added to the treatment armamentarium in the field of IBD. Overall, gut-associated lymphoid tissue plays a key role in IBD immunopathogenesis, which could offer novel therapeutic targets.

Patients with peritoneal metastasized colorectal cancer (PM-CRC) have a dismal prognosis. We hypothesized that an immunosuppressive environment in the peritoneal cavity underlies poor prognosis. We define the composition of the human peritoneal immune system (PerIS) using single-cell technologies in 18 patients with- and without PM-CRC, as well as in matched peritoneal metastases (n = 8). Here we show that the PerIS contains abundant immunosuppressive C1Q⁺VSIG4⁺ and SPP1⁺VSIG4⁺ peritoneal-resident macrophages (PRMs), as well as monocyte-like cavity macrophages (mono-CMs), which share features with tumor-associated macrophages, even in homeostasis. In PM-CRC, expression of immunosuppressive cytokines IL10 and VEGF increases, while simultaneously expression of antigen-presenting molecules decreases in PRMs. These intratumoral suppressive PRMs originate from the PerIS, and intraperitoneal depletion of PRMs in vivo using anti-CSF1R combined with anti-PD1 significantly reduces tumor burden and improves survival. Thus, PRMs define a metastatic site-specific immunosuppressive niche, and targeting PRMs is a promising treatment strategy for PM-CRC.