Microbiota-Propelled T Helper 17 Cells in Inflammatory Diseases and Cancer

Abstract

Technologies allowing genetic sequencing of the human microbiome are opening new realms to discovery. The host microbiota substantially impacts immune responses both in immune-mediated inflammatory diseases (IMIDs) and in tumors affecting tissues beyond skin and mucosae. However, a mechanistic link between host microbiota and cancer or IMIDs has not been well established. Here, we propose T helper 17 (T_H17) lymphocytes as the connecting factor between host microbiota and rheumatoid or psoriatic arthritides, multiple sclerosis, breast or ovarian cancer, and multiple myeloma. We theorize that similar mechanisms favor the expansion of gut-borne T_H17 cells and their deployment at the site of inflammation in extraborder IMIDs and tumors, where T_H17 cells are driving forces. Thus, from a pathogenic standpoint, tumors may share mechanistic routes with IMIDs. A review of similarities and divergences in microbiota-T_H17 cell interactions in IMIDs and cancer sheds light on previously ignored pathways in either one of the two groups of pathologies and identifies novel therapeutic avenues.

Keywords: IL-17; IL-22; Prevotella; T helper; T helper 17; T helper cells; TH17; autoimmunity; breast cancer; cancer; cancer immunology; cancer immunotherapy; immune checkpoint; immune-mediated inflammatory disease; microbiome; microbiota; multiple myeloma; multiple sclerosis; ovarian cancer; psoriasis; regulatory T cells; rheumatoid arthritis; tumor immunology.

FIG 1

Proinflammatory and anti-inflammatory activities of Prevotella in IMIDs and cancer. The abundance of P. histicola and Prevotella melaninogenica in the guts of preclinical models and humans or their colonization of the mouse gut is associated with decreased proinflammatory T_H17 cells in the intestine, joints, central nervous system, and bone marrow, leading to suppression of arthritis (43), amelioration of EAE (68), absence of MS (67), and delayed MM progression (22), respectively. In lungs, P. melaninogenica showed a profibrotic activity through the induction of T_H17 cells (211). Conversely, P. heparinolytica enhanced the progression of multiple myeloma in mice by inducing the local differentiation of T_H17 cells that migrated to the bone marrow and supported plasma cell survival (22). Prevotella intermedia and P. nigrescens were found to be abundant in the subgingival dental plaque and synovial fluid of patients affected by periodontitis and rheumatoid arthritis and associated with induction of T_H17 cells in these compartments and with disease progression (39). Prevotella bivia was found in every scored case of vaginosis, and the bacterial load positively correlated with the severity of the symptoms. Mechanistically, P. bivia activated NF-κB and the production of MIP-3α, RANTES, and IL-8, which induced local recruitment of T_H17 cells and neutrophils (212). P. copri and Prevotella spp. were associated with both T_H17 and T_H1 responses. Abundance of P. copri correlated with onset of newly diagnosed rheumatoid arthritis (37) and favored insulin resistance by increasing levels of branched-chain amino acids (213) and T_H17 and T_H1 inflammatory responses. Prevotella spp. exacerbated hepatic steatosis and inflammation in the liver in a TNF-α-dependent manner, thus driving progression of nonalcoholic steatohepatitis (214). In the colon, Prevotella spp. sustained the protumorigenic effect of dextran sodium sulfate (DSS) by favoring T_H17 and T_H1 immunity (215).

FIG 2

Potential mechanisms by which commensal bacteria induce activation of autoreactive or tumor-specific T cells in target tissues. The cartoon depicts several potential mechanisms by which the gut microbiota activates T_H17 lymphocytes, which migrate to the target tissue (the bone marrow in this case) and become triggered locally to release IL-17, thus promoting survival and proliferation of neoplastic plasma cells (MM). Dysbiosis or damage of the intestinal epithelium favors translocation of bacteria (176) that are picked up by dendritic cells (DCs). DCs may also pick up bacteria in the gut lumen. Bacterium-derived metabolites and bacterial fragments are collected by DCs, which are induced to maturation by inflammatory and other soluble factors released as a consequence of epithelial cell death. In the lamina propria, Payer’s patches, or mesenteric lymph nodes, DCs activate bacterium-specific T cells toward a T_H17 phenotype, thus limiting the expansion of regulatory T cells (Tregs) (10). Bacterium-specific T_H17 cells travel through the bloodstream into the bone marrow. Here, resident DCs also may pick up translocated bacteria or bacterial fragments, as well as tumor antigens released by dying plasma cells, and are induced to maturation toward a pro-T_H17 phenotype by inflammatory factors released as consequence of dysbiosis or by microbiota-derived metabolites, such as ATP (125) or long-chain fatty acids (189). In the bone marrow of MM patients, bacterium-specific T_H17 cells may cross-react against MM-associated antigens (158). Alternatively, MM-specific and/or passenger T_H17 cells (178) become activated in the bone marrow to release IL-17 by unspecific signals associated with inflammation (64, 172, 173). An additional possibility is that bacterium-specific T_H17 cells activated in the gut and deployed to the bone marrow also bear a second TCR specific for an MM-associated antigen (183).

FIG 3

IL-17R is upregulated in cancer versus healthy samples. mRNA expression of IL-17RA in primary metastatic colon adenocarcinoma cells from a cohort of 13 patients and matched colon (n = 28) and liver (n = 13) controls as described in reference , in primary invasive lobular breast cancer cells from 36 patients and 61 adjacent matched controls (breast) as described in The Cancer Genome Atlas (B), in 69 patient-derived primary prostate adenocarcinoma samples and 20 adjacent normal prostate samples (prostate gland) as described in reference (C), in primary ovarian cancer cells from a cohort of 185 patients and 10 normal ovarian surface epithelium samples (ovarian epithelium) as described in reference (D), in primary anaplastic large cell lymphoma cells from 6 patients and normal lymphocyte controls (CD4⁺ T cells, CD8⁺ T cells, and lymphocytes) as described in reference (E), and in 22 newly diagnosed MGUS patients, 12 SMM patients, and 22 matched controls (bone marrow) as described in reference (F). The expression patterns for the probe set AW029299, A_23_P17706, and 205707_at are shown. The results of statistical analysis (Student’s t test) are reported.