Abstract
Background and aimGut microbiota (GM) can support colorectal cancer (CRC) progression by modulating immune responses through the production of both immunostimulatory and/or immunosuppressive cytokines. The role of IL-9 is paradigmatic because it can either promote tumor progression in hematological malignancies or inhibit tumorigenesis in solid cancers. Therefore, we investigate the microbiota–immunity axis in healthy and tumor mucosa, focusing on the correlation between cytokine profile and GM signature.MethodsIn this observational study, we collected tumor (CRC) and healthy (CRC-S) mucosa samples from 45 CRC patients, who were undergoing surgery in 2018 at the Careggi University Hospital (Florence, Italy). First, we characterized the tissue infiltrating lymphocyte subset profile and the GM composition. Subsequently, we evaluated the CRC and CRC-S molecular inflammatory response and correlated this profile with GM composition, using Dirichlet multinomial regression.ResultsCRC samples displayed higher percentages of Th17, Th2, and Tregs. Moreover, CRC tissues showed significantly higher levels of MIP-1α, IL-1α, IL-1β, IL-2, IP-10, IL-6, IL-8, IL-17A, IFN-γ, TNF-α, MCP-1, P-selectin, and IL-9. Compared to CRC-S, CRC samples also showed significantly higher levels of the following genera: Fusobacteria, Proteobacteria, Fusobacterium, Ruminococcus2, and Ruminococcus. Finally, the abundance of Prevotella spp. in CRC samples negatively correlated with IL-17A and positively with IL-9. On the contrary, Bacteroides spp. presence negatively correlated with IL-9.ConclusionsOur data consolidate antitumor immunity impairment and the presence of a distinct microbiota profile in the tumor microenvironment compared with the healthy mucosa counterpart. Relating the CRC cytokine profile with GM composition, we confirm the presence of bidirectional crosstalk between the immune response and the host’s commensal microorganisms. Indeed, we document, for the first time, that Prevotella spp. and Bacteroides spp. are, respectively, positively and negatively correlated with IL-9, whose role in CRC development is still under debate.
Highlights
Colorectal cancer (CRC) is a complex and widespread disease and is the second cause of cancer-related deaths in the world (1)
Our study aims to investigate immune system–microbiota crosstalk in CRC through the cellular and molecular characterization of immunity and the comparative evaluation of microbiota composition in healthy and tumor mucosa, focusing on the correlation between the cytokine profile and gut microbiota (GM) composition
We performed polychromatic flow cytometry analysis of Tissue Infiltrating Lymphocytes (TILs) isolated from the dissociated CRC and CRC-S
Summary
Colorectal cancer (CRC) is a complex and widespread disease and is the second cause of cancer-related deaths in the world (1). Chronic inflammation increases cancer risk through a deregulated activation of the immune system, which causes a loss of tissue architecture and genotoxic cellular DNA damage (5) In this context, CRC is considered the best example of a chronic inflammation–associated tumor, occurring often in patients with inflammatory bowel disease (IBD): IBD-associated CRC is estimated to be 2% of all CRCs, and the rate of death resulting from CRC in IBD patients ranges from 10% to 15% (6, 7). The protective immunity is mediated by effector cells (Th1 and Th17/Th1), and “not effector” T lymphocyte subsets (Th2, Tregs, Tnull) can promote colon cancer progression (9–11) In this scenario, the microbiota plays an important role as well because it is essential to modulate immune responses favoring the equilibrium between protective immunity and tolerance to commensal bacteria (12). We investigate the microbiota–immunity axis in healthy and tumor mucosa, focusing on the correlation between cytokine profile and GM signature
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