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Simple Summary: Inflammation of the colon (colitis) can increase the risk of developing colorectal cancers. Gut microbiota may play a role in the development of this cancer. One potential way to prevent this cancer is to manipulate the community of bacteria in the colon. In a study using mice, we found that transferring the bacteria from the bedding of healthy mice to those with colitis increased the presence of Akkermansia, which may help reduce inflammation in the colon. Meanwhile, untreated mice had an increase in other types of bacteria, such as Anaeroplasma and Alistipes, which may contribute to inflammation. These findings suggest that certain types of bacteria may help reduce inflammation in the colon and prevent cancer. Chronic inflammation of the colon (colitis) is a known risk factor for inflammatory-driven colorectal cancers (id-CRCs), and intestinal microbiota has been implicated in the etiology of id-CRCs. Manipulation of the microbiome is a clinically viable therapeutic approach to limiting id-CRCs. To understand the microbiome changes that occur over time in id-CRCs, we used a mouse model of id-CRCs with the treatment of azoxymethane (AOM) and dextran sodium sulfate (DSS) and measured the microbiome over time. We included cohorts where the microbiome was restored using cage bedding swapping and where the microbiome was depleted using antibiotics to compare to untreated animals. We identified consistent increases in Akkermansia in mice receiving horizontal microbiome transfer (HMT) via cage bedding swapping, while the control cohort had consistent longitudinal increases in Anaeroplasma and Alistipes. Additionally, fecal lipocalin-2 (Lcn-2), a marker of intestinal inflammation, was elevated in unrestored animals compared to restored and antibiotic-treated counterparts following HMT. These observations suggest a potential role for Akkermansia, Anaeroplasma, and Alistipes in regulating colonic inflammation in id-CRCs. [ABSTRACT FROM AUTHOR]

Worldwide, colorectal cancer (CRC) is one of the leading causes of cancer-related deaths. Recent advances in high-throughput technologies have shown that the gut microbiota may have a major influence on human health, including CRC. Nonetheless, how the gut microbiota interacts with tumor cells in CRC patients is largely unknown. Studies have shown that the microbiota fills in a variety of niche metabolic pathways that the host does not possess. For example, the microbiota produces butyrate, which provides the colon's epithelial cells with about 70% of their energy needs. The typically fast proliferation of tumor cells in CRC patients drastically alters the tumor's nutrient microenvironment. Those alterations correspond to the microbiota composition and functional changes. In tumor cells, a central mediator of metabolic changes is the aberrant expression of microRNAs (miRNAs). In this study, we explored recent insights into metabolic interactions between the microbiota and tumor cells in CRC pathobiology, focusing on the role of miRNAs. These observations support our view that miRNAs may also serve as mediators of the metabolites' effects. [ABSTRACT FROM AUTHOR]

Despite significant advances over the past 2 decades in preventive screening and therapy aimed at improving patient survival, colorectal cancer (CRC) remains the second most common cause of cancer death in the United States. The average 5-year survival rate of CRC patients with positive regional lymph nodes is only 40%, while less than 5% of patients with distant metastases survive beyond 5 years. There is a critical need to develop novel therapies that can improve overall survival in patients with poor prognoses, particularly since 60% of them are diagnosed at an advanced stage. Pertinently, immune checkpoint blockade therapy has dramatically changed how we treat CRC patients with microsatellite-instable high tumors. Furthermore, accumulating evidence shows that changes in gut microbiota are associated with the regulation of host antitumor immune response and cancer progression. Appropriate animal models are essential to deciphering the complex mechanisms of host antitumor immune response and tumor-gut microbiome metabolic interactions. Here, we discuss various mouse models of colorectal cancer that are developed to address key questions on tumor immune response and tumor-microbiota interactions. These CRC models will also serve as resourceful tools for effective preclinical studies. [Display omitted] [ABSTRACT FROM AUTHOR]

Simple Summary: Our study demonstrated that Atypical Chemokine Receptor 4 (ACKR4) was downregulated in human colorectal cancer (CRC) compared with normal colon tissues. Loss of ACKR4 in human CRC was associated with a weak anti-tumor immune response. Knockdown of ACKR4 in tumor cells impairs the dendritic cell migration from the tumor to the tumor-draining lymph nodes (TdLNs), causing inadequate tumor-specific T-cell expansion and insensitivity to immune checkpoint blockades. However, loss of ACKR4 in stromal cells does not significantly affect anti-tumor immunity. In human CRC, high expression of microRNA-552 was a mechanism leading to ACKR4 downregulation. Our study revealed a novel mechanism that leads to the poor immune response in a subset of CRC and will contribute to the framework for identifying new therapies against this deadly cancer. Colorectal cancer (CRC) is one of the most common malignancies in both morbidity and mortality. Immune checkpoint blockade (ICB) treatments have been successful in a portion of mismatch repair-deficient (dMMR) CRC patients but have failed in mismatch repair-proficient (pMMR) CRC patients. Atypical Chemokine Receptor 4 (ACKR4) is implicated in regulating dendritic cell (DC) migration. However, the roles of ACKR4 in CRC development and anti-tumor immunoregulation are not known. By analyzing human CRC tissues, transgenic animals, and genetically modified CRC cells lines, our study revealed an important function of ACKR4 in maintaining CRC immune response. Loss of ACKR4 in CRC is associated with poor immune infiltration in the tumor microenvironment. More importantly, loss of ACKR4 in CRC tumor cells, rather than stromal cells, restrains the DC migration and antigen presentation to the tumor-draining lymph nodes (TdLNs). Moreover, tumors with ACKR4 knockdown become less sensitive to immune checkpoint blockade. Finally, we identified that microRNA miR-552 negatively regulates ACKR4 expression in human CRC. Taken together, our studies identified a novel and crucial mechanism for the maintenance of the DC-mediated T-cell priming in the TdLNs. These new findings demonstrate a novel mechanism leading to immunosuppression and ICB treatment resistance in CRC. [ABSTRACT FROM AUTHOR]

Colorectal cancer is a major cause of cancer-related deaths worldwide. Immune checkpoint blockade therapies are effective in 30%–60% of the microsatellite instable–high subtype. Unfortunately, most patients with colorectal cancer (>85%) have microsatellite stable tumors that do not respond. In this study, we aimed to decipher the underlying tumor-intrinsic mechanisms critical for improving immunotherapy in colorectal cancer. We used human and mouse tumor samples, cell lines, human colorectal cancer organoids, and various syngeneic orthotopic mouse models of late-stage colorectal cancer to define the effects of tumor cell–secreted extracellular vesicles (EVs) on antitumor immune response. Our analyses of human colorectal cancer immune profiles and tumor–immune cell interactions showed that tumor-secreted EVs containing microRNA miR-424 suppressed the CD28-CD80/86 costimulatory pathway in tumor-infiltrating T cells and dendritic cells, leading to immune checkpoint blockade resistance. Modified tumor-secreted EVs with miR-424 knocked down enhanced T-cell–mediated antitumor immune response in colorectal cancer tumor models and increased the immune checkpoint blockade response. Intravenous injections of modified tumor-secreted EVs induced tumor antigen–specific immune responses and boosted the immune checkpoint blockade efficacy in colorectal cancer models that mimic aggressively progressing, late-stage disease. Collectively, we show a critical role for tumor-secreted EVs in antitumor immune regulation and immunotherapy response, which could be developed as a novel treatment for immune checkpoint blockade–resistant colorectal cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

Changes in gut microbiota composition have consistently been observed in patients with colorectal cancer (CRC). Yet, it is not entirely clear how the gut microbiota interacts with tumor cells. We know that tumor cells undergo a drastic change in energy metabolism, mediated by microRNAs (miRNAs), and that tumor-derived miRNAs affect the stromal and immune cell fractions of the tumor microenvironment. Recent studies suggest that host intestinal miRNAs can also affect the growth and composition of the gut microbiota. Our previous CRC studies showed a high-level of interconnectedness between host miRNAs and their microbiota. Considering all the evidence to date, we postulate that the altered nutrient composition and miRNA expression in the CRC microenvironment selectively exerts pressure on the surrounding microbiota, leading to alterations in its composition. In this review article, we present our current understanding of the role of miRNAs in mediating host–microbiota interactions in CRC. [ABSTRACT FROM AUTHOR]