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Background and aimsThe role of inflammatory immune responses in colorectal cancer (CRC) development and response to therapy is a matter of intense debate. While inflammation is a known driver of CRC, inflammatory immune infiltrates are a positive prognostic factor in CRC and predispose to response to immune checkpoint blockade (ICB) therapy. Unfortunately, over 85% of CRC cases are primarily unresponsive to ICB due to the absence of an immune infiltrate, and even the cases that show an initial immune infiltration can become refractory to ICB. The identification of therapy supportive immune responses in the field has been partially hindered by the sparsity of suitable mouse models to recapitulate the human disease. In this study, we aimed to understand how the dysregulation of the complement anaphylatoxin C3a receptor (C3aR), observed in subsets of patients with CRC, affects the immune responses, the development of CRC, and response to ICB therapy.MethodsWe use a comprehensive approach encompassing analysis of publicly available human CRC datasets, inflammation-driven and newly generated spontaneous mouse models of CRC, and multiplatform high-dimensional analysis of immune responses using microbiota sequencing, RNA sequencing, and mass cytometry.ResultsWe found that patients’ regulation of the complement C3aR is associated with epigenetic modifications. Specifically, downregulation of C3ar1 in human CRC promotes a tumor microenvironment characterized by the accumulation of innate and adaptive immune cells that support antitumor immunity. In addition, in vivo studies in our newly generated mouse model revealed that the lack of C3a in the colon activates a microbiota-mediated proinflammatory program which promotes the development of tumors with an immune signature that renders them responsive to the ICB therapy.ConclusionsOur findings reveal that C3aR may act as a previously unrecognized checkpoint to enhance antitumor immunity in CRC. C3aR can thus be exploited to overcome ICB resistance in a larger group of patients with CRC.

The secretory immunoglobulin A (SIgA) in mammalian gut protects the organism from infections and contributes to host physiology by shaping microbiota composition. The mechanisms regulating the adaptive SIgA response towards gut microbes are poorly defined. Deletion of P2rx7, encoding for the ATP-gated ionotropic P2X7 receptor, leads to T follicular helper (Tfh) cells expansion in the Peyer’s patches (PPs) of the small intestine, enhanced germinal centre (GC) reaction and IgA secretion; the resulting alterations of the gut microbiota in turn affects host metabolism. Here, we define gut microbiota modifications that correlate with deregulated SIgA secretion and metabolic alterations in P2rx7−/− mice. In particular, Lactobacillus shows enhanced SIgA coating in P2rx7−/− with respect to wild-type (WT) mice. The abundance of SIgA-coated lactobacilli positively correlates with Tfh cells number and body weight, suggesting Lactobacillus-specific SIgA response conditions host metabolism. Accordingly, oral administration of intestinal Lactobacillus isolates from P2rx7−/− mice to WT animals results in altered glucose homeostasis and fat deposition. Thus, enhanced SIgA production by P2X7 insufficiency promotes Lactobacillus colonization that interferes with systemic metabolic homeostasis. These data indicate that P2X7 receptor-mediated regulation of commensals coating by SIgA is important in tuning the selection of bacterial taxa, which condition host metabolism.

Jellyfish represent an important component of marine food webs characterized by large fluctuations of population density, with the ability to abruptly form outbreaks, followed by rarity periods. In spite of considerable efforts to investigate how jellyfish populations are responding globally to anthropogenic change, available evidence still remains unclear. In the last 50 years, jellyfish arc seemingly on the rise in a number of coastal areas, including the Mediterranean Sea, where jellyfish blooms periodically become an issue to marine and maritime human activities. Their impacts on marine organism welfare have been poorly quantified. The jellyfish, Rhizostoma pulmo, is an outbreak-forming scyphomedusa whose large populations spread across the Mediterranean, with increasing periodicity and variable abundance. Studies on cnidarian jellyfish suggested being important vectors of bacterial pathogens. In the present study, by combination of conventional culture-based methods and a high-throughput amplicon sequencing (HTS) approach, we characterized the diversity of the bacterial community associated with this jellyfish during their summer outbreak. Three distinct jellyfish compartments, namely umbrella, oral arms, and the mucus secretion obtained from whole specimens were screened for specifically associated microbiota. A total of 17 phyla, 30 classes, 73 orders, 146 families and 329 genera of microbial organisms were represented in R. pulmo samples with three major lades (ie. Spiroplasma, Mycoplasma and Wolinella) representing over 90% of the retrieved total sequences. The taxonomic microbial inventory was then combined with metabolic profiling data obtained from the Biolog Eco-Plate system. Significant differences among the jellyfish compartments were detected in terms of bacterial abundance, diversity and metabolic utilization of 31 different carbon sources with the highest value of abundance and metabolic potential in the mucus secretion compared to the umbrella and oral arms. Results are discussed in the framework of the species ecology as well as the potential health hazard for marine organisms and humans. (C) 2019 Elsevier B.V. All rights reserved.