Enterotoxigenic Bacteroides fragilis (ETBF), a human commensal and candidate pathogen in colorectal cancer (CRC), is a potent initiator of interleukin-17 (IL-17)-dependent colon tumorigenesis in Min
...mice. We examined the role of IL-17 and ETBF on the differentiation of myeloid cells into myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages, which are known to promote tumorigenesis. The myeloid compartment associated with ETBF-induced colon tumorigenesis in Min mice was defined using flow cytometry and gene expression profiling. Cell-sorted immature myeloid cells were functionally assayed for inhibition of T-cell proliferation and inducible nitric oxide synthase expression to delineate MDSC populations. A comparison of ETBF infection with that of other oncogenic bacteria (Fusobacterium nucleatum or pks
Escherichia coli) revealed a specific, ETBF-associated colonic immune infiltrate. ETBF-triggered colon tumorigenesis is associated with an IL-17-driven myeloid signature characterized by subversion of steady-state myelopoiesis in favor of the generation of protumoral monocytic-MDSCs (MO-MDSCs). Combined action of the B. fragilis enterotoxin BFT and IL-17 on colonic epithelial cells promoted the differentiation of MO-MDSCs, which selectively upregulated Arg1 and Nos2, produced NO, and suppressed T-cell proliferation. Evidence of a pathogenic inflammatory signature in humans colonized with ETBF may allow for the identification of populations at risk for developing colon cancer.
Since their recent discovery, T helper 17 (Th17) cells have been frequently detected in the tumor microenvironment of many malignancies, but their clinical implications remain largely unknown. ...Interleukin-17 (IL-17) detection is commonly related with poor outcomes in colorectal cancers, yet its presence is associated with antitumor responses in ovarian carcinomas. Numerous experimental models illustrate the divergent roles of Th17 cells in tumor immunity, which appears to be mainly dependent on the tumor context (type, location, and stage of cancer). It is recognized that IL-17 is produced by a variety of cell types and that Th17 cells are endowed with a unique functional plasticity. Therefore, when trying to elucidate potential immune biomarkers and immunotargets, it is extremely important to make a clear dissociation between strategies targeting Th17 versus its hallmark cytokine, IL-17. In this review, we will summarize the data regarding the detection of IL-17 and Th17 in human cancers, consider the experimental evidence on their respective roles in antitumor activity, and discuss the potential of IL-17 as an immune target for therapeutic interventions.
Tumor-derived extracellular vesicles (EVs) have been associated with immune evasion and tumor progression. We show that the RNA-sensing receptor RIG-I within tumor cells governs biogenesis and ...immunomodulatory function of EVs. Cancer-intrinsic RIG-I activation releases EVs, which mediate dendritic cell maturation and T cell antitumor immunity, synergizing with immune checkpoint blockade. Intact RIG-I, autocrine interferon signaling, and the GTPase Rab27a in tumor cells are required for biogenesis of immunostimulatory EVs. Active intrinsic RIG-I signaling governs composition of the tumor EV RNA cargo including small non-coding stimulatory RNAs. High transcriptional activity of EV pathway genes and RIG-I in melanoma samples associate with prolonged patient survival and beneficial response to immunotherapy. EVs generated from human melanoma after RIG-I stimulation induce potent antigen-specific T cell responses. We thus define a molecular pathway that can be targeted in tumors to favorably alter EV immunomodulatory function. We propose “reprogramming” of tumor EVs as a personalized strategy for T cell-mediated cancer immunotherapy.
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RIG-I activity regulates biogenesis and function of tumor cell-derived EVs
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Cancer-intrinsic RIG-I signaling governs the composition of the EV RNA cargo
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Immunostimulatory EVs trigger T cell-based antitumor immunity in mice and humans
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EV and RIG-I gene signatures in melanomas correlate with response to immunotherapy
Extracellular vesicles harbor extraordinary potential for cancer therapy, but one limitation is an inadequate understanding of signaling pathways that regulate their biogenesis and function. Heidegger et al. define a tumor-intrinsic molecular pathway that can be targeted to modulate tumor EV cargo constituents and thus their immunomodulatory potential on T cell immunity.
Pro-carcinogenic bacteria have the potential to initiate and/or promote colon cancer, in part via immune mechanisms that are incompletely understood. Using ApcMin mice colonized with the ...human pathobiont enterotoxigenic Bacteroides fragilis (ETBF) as a model of microbe-induced colon tumorigenesis, we show that the Bacteroides fragilis toxin (BFT) triggers a pro-carcinogenic, multi-step inflammatory cascade requiring IL-17R, NF-κB, and Stat3 signaling in colonic epithelial cells (CECs). Although necessary, Stat3 activation in CECs is not sufficient to trigger ETBF colon tumorigenesis. Notably, IL-17-dependent NF-κB activation in CECs induces a proximal to distal mucosal gradient of C-X-C chemokines, including CXCL1, that mediates the recruitment of CXCR2-expressing polymorphonuclear immature myeloid cells with parallel onset of ETBF-mediated distal colon tumorigenesis. Thus, BFT induces a pro-carcinogenic signaling relay from the CEC to a mucosal Th17 response that results in selective NF-κB activation in distal colon CECs, which collectively triggers myeloid-cell-dependent distal colon tumorigenesis.
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•B. fragilis toxin-induced tumorigenesis requires epithelial IL17 and Stat3 signaling•IL17 targets colonic epithelial cells (CECs) to promote ETBF-mediated carcinogenesis•IL17-activated NF-κb signaling in CECs triggers C-X-C chemokine expression•NF-κB-induced chemokines direct pro-tumoral myeloid infiltration to distal colon
Chung et al. uncover a complex, microbe-driven carcinogenic mechanism whereby the Bacteroides fragilis toxin targets the colonic epithelium to trigger an IL-17 mucosal immune response that relays back to epithelial cells, inciting pro-tumoral myeloid cell infiltration, principally to the distal colon, corresponding to the region of tumorigenesis in ApcMin/− mice.
Recent studies highlight immunoregulatory functions of type I interferons (IFN-I) during the pathogenesis of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation ...(allo-HSCT). We demonstrated that selective activation of IFN-I pathways including RIG-I/MAVS and cGAS/STING prior to allo-HSCT conditioning therapy can ameliorate the course of GVHD. However, direct effects of IFN-Is on immune cells remain ill characterized. We applied RIG-I agonists (3pRNA) to stimulate IFN-I production in murine models of conditioning therapy with total body irradiation (TBI) and GVHD. Using IFN-I receptor-deficient donor T cells and hematopoietic cells, we found that endogenous and RIG-I-induced IFN-Is do not reduce GVHD by acting on these cell types. However, 3pRNA applied before conditioning therapy reduced the ability of CD11c
recipient cells to stimulate proliferation and interferon gamma expression of allogeneic T cells. Consistently, RIG-I activation before TBI reduced the proliferation of transplanted allogeneic T-cells. The reduced allogenicity of CD11c
recipient cells was dependent on IFN-I signaling. Notably, this immunosuppressive function of DCs was restricted to a scenario where tissue damage occurs. Our findings uncover a context (damage by TBI) and IFN-I dependent modulation of T cells by DCs and extend the understanding about the cellular targets of IFN-I during allo-HSCT and GVHD.
Deficiency in X-linked inhibitor of apoptosis protein (XIAP) is the cause for X-linked lymphoproliferative syndrome 2 (XLP2). About one-third of these patients suffer from severe and ...therapy-refractory inflammatory bowel disease (IBD), but the exact cause of this pathogenesis remains undefined. Here, we used XIAP-deficient mice to characterize the mechanisms underlying intestinal inflammation. In
mice, we observed spontaneous terminal ileitis and microbial dysbiosis characterized by a reduction of
species. We showed that in inflamed mice, both TNF receptor 1 and 2 (TNFR1/2) cooperated in promoting ileitis by targeting TLR5-expressing Paneth cells (PCs) or dendritic cells (DCs). Using intestinal organoids and in vivo modeling, we demonstrated that TLR5 signaling triggered TNF production, which induced PC dysfunction mediated by TNFR1. TNFR2 acted upon lamina propria immune cells. scRNA-seq identified a DC population expressing TLR5, in which
expression was also elevated. Thus, the combined activity of TLR5 and TNFR2 signaling may be responsible for DC loss in lamina propria of
mice. Consequently, both
and
mice were rescued from dysbiosis and intestinal inflammation. Furthermore, RNA-seq of ileal crypts revealed that in inflamed
mice, TLR5 signaling was abrogated, linking aberrant TNF responses with the development of a dysbiosis. Evidence for TNFR2 signaling driving intestinal inflammation was detected in XLP2 patient samples. Together, these data point toward a key role of XIAP in mediating resilience of TLR5-expressing PCs and intestinal DCs, allowing them to maintain tissue integrity and microbiota homeostasis.
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