Role of inflammation, innate resistance, and immunity in carcinogenesis

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Myeloid differentiation factor 88 (Myd88) is an important signaling molecule which contributes to signal transduction triggered by microbial products via recognition mediated by members of the Toll-like receptor and IL-1 receptor families. Using the azoxymethane (AOM)/DSS model of colitis-associated colorectal cancer, we previously showed that Myd88-/- mice are unable to heal colonic ulcers thereby increasing perpetuating the inflammatory microenvironment and fostering the dramatic increase in adenoma and adenocarcinoma formation in the colon. In this study, we decipher the compartment responsible for driving the anti-tumorigenic effects of MyD88. We hypothesized that MyD88 signaling from Cd11b+ myeloid cells mediates anti-tumor responses in the colon by reducing myeloid cell infiltration into the lamina propria and by preventing the expansion of GUS-type beta-glucuronidase- and invasin-containing microbes. Indeed, deletion of Myd88 in Cd11b+ cells (Myd88CD11b-/- mice) increased the number of adenomas formed relative to their corresponding floxed littermate controls. Remarkably, wild type mice co-housed with Myd88CD11b-/- animals or recipients of microbial transfer from these animals developed greater polyps in quantity and size. Taken together, MyD88 signaling in myeloid cells favors the development of a protective anti-tumoral response from the host and the gut microbiota. Oral fungal infection impacts epithelial innate immunity to promote local and distal tumor growth: Fungi reside within tumors, however, the mechanisms by which they evade immunity remains unsettled. In mice that lack epithelial expression of the immune protein IKK alpha, oral infection with the Cladosporium cladosporioides fungi increases their colonization and development of both oral and skin squamous cell carcinoma (SCC). Fungal-induced intratumoral STAT3 signaling generates acidic metabolites in the oral cavity that repress the antifungal phagocytic activity of neutrophils and, in conjunction with skin macrophages, increase IL-1b-inflammatory signature. Oral fungal infection also induces systemic IL-1b/IL-17A that enhance skin carcinogenesis. Blocking epithelial-cell-STAT3 signaling resets innate immune responses and prevents both fungal growth and IL-1b expression. Neutralization of IL-1b inhibits skin tumor growth enhancement by oral fungus infection. Consistently, advanced human head and neck SCCs that are infiltrated by neutrophils expressing High-IL1B/Low-phagocytic signatures have been found to be colonized by fungi. Collectively our findings reveal novel mechanisms of cooperation between epithelial and innate immune cells leading to resistance to both fungal infection and cancer development. CSF-1R+ Macrophages Control the Gut Microbiome-Enhanced Liver Invariant NKT Function through IL-18: altering the gut microbiome by oral vancomycin increases liver invariant NKT (iNKT) cell function. Enhanced iNKT cytokine production and activation marker expression were observed in vancomycin-treated mice following both Ag-specific and Ag-independent in vivo iNKT stimulations, with a more prominent effect in the liver than in the spleen. Fecal transplantation studies demonstrated that the iNKT functional regulation is mediated by altering the gut microbiome but uncoupled from the modulation of iNKT cell population size. Interestingly, when stimulated in vitro, iNKT cells from vancomycin-treated mice did not show increased activation, suggesting an indirect regulation. iNKT cells expressed high levels of IL-18 receptor, and vancomycin increased the expression of IL-18 in the liver. Blocking IL-18 by neutralizing Ab or using genetically deficient mice attenuated the enhanced iNKT activation. Liver macrophages were identified as a major source of IL-18. General macrophage depletion by clodronate abolished this iNKT activation. Using anti-CSF-1R depletion or LyzCrexCSF-1RLsL-DTR mice identified CSF-1R+ macrophages as a critical modulator of iNKT function. Vancomycin treatment had no effect on iNKT cell function in vivo in IL-18 knockout macrophage reconstituted mice. Together, our results demonstrate that the gut microbiome controls liver iNKT function via regulating CSF-1R+ macrophages to produce IL-18. Targeting the triggering receptor expressed on myeloid cell 1 (TREM1) augments antitumor T cell immunity by inhibiting myeloid-derived suppressor cells and restraining anti-PD-1 resistance: TREM1 plays a critical role in development of chronic inflammatory disorders and the inflamed tumor microenvironment (TME) associated with most solid tumors. We examined whether loss of TREM1 signaling can abrogate the immunosuppressive TME and enhance cancer immunity. To investigate the therapeutic potential of TREM1 in cancer, we used mice deficient in Trem1 and developed a novel small molecule TREM1 inhibitor, VJDT. We demonstrated that genetic or pharmacological TREM1 silencing significantly delayed tumor growth in murine melanoma (B16F10) and fibrosarcoma (MCA205) models. Single-cell RNA-Seq combined with functional assays during TREM1 deficiency revealed decreased immunosuppressive capacity of myeloid-derived suppressor cells (MDSCs) accompanied by expansion in cytotoxic CD8+ T cells and increased PD-1 expression. Furthermore, TREM1 inhibition enhanced the antitumorigenic effect of anti-PD-1 treatment, in part, by limiting MDSC frequency and abrogating T cell exhaustion. In patient-derived melanoma xenograft tumors, treatment with VJDT downregulated key oncogenic signaling pathways involved in cell proliferation, migration, and survival. Our work highlights the role of TREM1 in cancer progression, both intrinsically expressed in cancer cells and extrinsically in the TME. Thus, targeting TREM1 to modify an immunosuppressive TME and improve efficacy of immune checkpoint therapy represents what we believe to be a promising therapeutic approach to cancer. The gut microbiome controls liver tumors via the vagus nerve: Liver cancer ranks amongst the deadliest cancers. Nerves have emerged as an understudied regulator of tumor progression. The parasympathetic vagus nerve influences systemic immunity via acetylcholine (ACh). Whether cholinergic neuroimmune interactions influence hepatocellular carcinoma (HCC) remains uncertain. Liver denervation via hepatic vagotomy (HV) significantly reduced liver tumor burden, while pharmacological enhancement of parasympathetic tone promoted tumor growth. Cholinergic disruption in Rag1KO mice revealed that cholinergic regulation requires adaptive immunity. Further scRNA-seq and in vitro studies indicated that vagal ACh dampens CD8+ T cell activity via muscarinic ACh receptor (AChR) CHRM3. Depletion of CD8+ T cells abrogated HV outcomes and selective deletion of Chrm3 on CD8+ T cells inhibited liver tumor growth. Beyond tumor-specific outcomes, vagotomy improved cancer associated fatigue and anxiety-like behavior. As microbiota transplantation from HCC donors was sufficient to impair behavior, we investigated putative microbiota-neuroimmune crosstalk. Tumor, rather than vagotomy, robustly altered fecal bacterial composition, incre associated microbiota to activate hepatic CD8+ T cells. These findings reveal that gut bacteria influence behavior and liver anti-tumor immunity via a dynamic and pharmaceutically targetable, vagus-liver axis.