Reciprocal influence of B cells and tumor macro and microenvironments in theApc^Min/+model of colorectal cancer

Abstract

One of the most fascinating aspects of the immune system is its dynamism, meant as the ability to change and readapt according to the organism needs. Following an insult, we assist to the spontaneous organization of different immune cells which cooperate, locally and at distance, to build up an appropriate response. Throughout tumor progression, adaptations within the systemic tumor environment, or macroenvironment, result in the promotion of tumor growth, tumor invasion and metastasis to distal organs, but also to dramatic changes in the activity and composition of the immune system. In this work, we show the changes of the B-cell arm of the immune system following tumor progression in the model of colorectal cancer. Tumor macroenvironment leads to an increased proportion of total and IL-10-competent B cells in draining LNs while activates a differentiation route that leads to the expansion of IgA lymphocytes in the spleen and peritoneum. Importantly, serum IgA levels were significantly higher in than Wt mice. The peculiar involvement of IgA response in the adenomatous transformation had correlates in the gut-mucosal compartment where IgA-positive elements increased from normal mucosa to areas of low grade dysplasia while decreasing upon overt carcinomatous transformation. Altogether, our findings provide a snapshot of the tumor education of B lymphocytes in the model of colorectal cancer. Understanding how tumor macroenvironment affects the differentiation, function and distribution of B lymphocytes is pivotal to the generation of specific therapies, targeted to switching B cells to an anti-, rather than pro-, tumoral phenotype.

Mast cells crosstalk with B cells in the gut and sustain IgA response in the inflamed intestine

“…This result was specific to the inflammatory condition since the simultaneous increase of activated MCs and PCs was not observed in the context of CRC. Indeed, all B cell populations considered in our analysis were less represented in the cancerous compared to the normal mucosa of CRC patients, which is in accordance with our recently published data showing the accumulation of IgA + elements in areas of low‐grade dysplasia and their extrusion from the adenoma tissue [26]. Altogether these data call for the need for a better understanding of this crosstalk that bridges the innate and adaptive immune system, with particular attention on the implications that this bidirectional interaction has on MC function.…”

“…Single‐cell suspensions of spleens, peritoneum, and LNs were obtained as previously described [26]. Peritoneal and splenic CD19 + B cells for B/MC co‐cultures were obtained using mouse CD19 MicroBeads (Miltenyi) while the B cell isolation kit (Miltenyi) was used to isolate B lymphocytes from total RMB splenocytes.…”

FoPA: identifying perturbed signaling pathways in clinical conditions using formal methods

“…Since IgA-secreting cells contribute to reducing inflammatory response which is a strong risk factor for the development of gastrointestinal adenocarcinomas, it is likely that the impairment of IgA production may drive further inflammatory responses and promote tumor growth. This is consistent with prior studies that showed the influence of IgA-secreting cells and B cells to colon tumors progression [59, 60].…”

Myeloid-Derived Suppressor Cells Produce IL-10 to Elicit DNMT3b-Dependent IRF8 Silencing to Promote Colitis-Associated Colon Tumorigenesis

“…Many of the proinflammatory cytokines are abundantly expressed in chronic inflammatory lesions and the tumor tissues, but it was reported that, unlike these proinflammatory cytokines, IL-10 is not expressed in tumor tissues ( Mumm et al, 2011 ). It is well known that IL-10 is expressed in B and T cells ( Dambuza et al, 2017 ; Mion et al, 2017 ; Yu et al, 2013 ). IL-10 is also expressed in myeloid cells such as MDSCs ( Hardbower et al, 2017 ; Shvedova et al, 2015 ) to promote tumor growth.…”