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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 unique life history features of seahorses (low mobility, site fidelity, low fecundity, high parental care) make them vulnerable to the environmental changes and anthropic pressures. Despite increasing concern over their conservation status, many biological and ecological aspects remain poorly documented therefore disabling and limiting management strategies. Most of the Mediterranean populations are threatened by human activities and a recent document drawn up by the Italian Committee of IUCN for marine fish of the Italian coasts defined the two species as Near Threatened (NT). During the last 15 years, despite the absence of specific funding projects and thanks to the large group of volunteers working alongside researchers, a considerable research group has been created, allowing investigation of several aspects of seahorse life cycle in an area that has never been studied before. In this period, we have conducted several studies on their spatial and temporal persistence, population structure, habitat preferences, and diet composition. Hippocampus guttulatus and H. hippocampus are two sympatric species distributed throughout the entire Mediterranean Sea. Thau lagoon was considered as the area with the highest seahorse density but, thanks to this research group, the importance of Taranto Mar Piccolo as a site of the extraordinary conservation interest has been highlighted. Both species display patchy distribution and a high spatial demographic heterogeneity despite the fact that the most abundant populations are unbalanced in terms of size classes, presumably indicating problems in the local recruitment or due to the anomalous mortality. They show a tendency for covered substrates (e.g. Corallina sp. and Cladophora sp. facies) offering complex and holdfast-rich microhabitats. Both species, however, can also exploit uncovered substrates as well as infralittoral habitats. The diet shows strong differences in diversity and abundance of preyed taxa related to the habitat of occurrence. Overall, amphipods, copepods and isopods are the major contributors to the diet. Although temporal persistence on a large scale was observed, indicating the capacity to resist and persist in time and space, seahorses are in a state of distress because of patchy distribution and unstructured populations. This, even more, highlights the need for suitable strategies to protect foraging habitats and ecosystems where there are numerous populations, like in Mar Piccolo of Taranto.

Background: The existence of age-associated alterations in immune functions and neuropeptides capable of modulating these functions prompted us to advance the hypothesis that the degradation of plasma neuropeptides, specifically opioid peptides, may be altered by aging. Objective: To verify the possible existence of age-induced variations in neuropeptide hydrolysis in human plasma, using leucine enkephalin as the model substrate. Methods: The hydrolysis of leucine enkephalin and the formation of its hydrolysis byproducts in the presence of plasma enzymes were studied by kinetic and chromatographic techniques in a group of elderly individuals and a control group. Results: The results obtained indicate that in elderly individuals the activity of enkephalin-degrading plasma enzymes is greater than in controls. ANOVA analysis of these data indicates that the dependency of the variation of hydrolysis upon the 2 age groups is statistically significant. Increased substrate hydrolysis, and a modified hydrolysis pattern, appear to be associated with increased activity of the enzymes involved, and with different distribution of the individual enzymes within each class, as well as with severely reduced activity of the low molecular weight plasma inhibitors. Conclusion: The combination of the above-mentioned factors appears to define a characteristic hydrolysis pattern for elderly individuals which is different from that found in controls.