COVID-19 rapidly emerged as a crippling public health crisis in the last few months, which has presented a series health risk. Understanding of the immune response and biomarker analysis is needed to progress toward understanding disease pathology and developing improved treatment options. The goal of this study is to identify pathogenic factors that are linked to disease severity and patient characteristics. Patients with COVID-19 who were hospitalized from March 17 to June 5, 2020 were analyzed for clinical features of disease and soluble plasma cytokines in association with disease severity and sex. Data from COVID-19 patients with acute illness were examined along with an age- and gender-matched control cohort. We identified a group of 16 soluble factors that were found to be increased in COVID-19 patients compared to controls, whereas 2 factors were decreased. In addition to inflammatory cytokines, we found significant increases in factors known to mediate vasculitis and vascular remodeling (PDGF-AA, PDGF-AB-BB, soluble CD40L (sCD40L), FGF, and IP10). Four factors such as platelet-derived growth factors, fibroblast growth factor-2, and IFN-γ-inducible protein 10 were strongly associated with severe disease and ICU admission. Th2-related factors (IL-4 and IL-13) were increased with IL-4 and sCD40L present at increased levels in males compared with females. Our analysis revealed networking clusters of cytokines and growth factors, including previously unknown roles of vascular and stromal remodeling, activation of the innate immunity, as well activation of type 2 immune responses in the immunopathogenesis of COVID-19. These data highlight biomarker associations with disease severity and sex in COVID-19 patients.

Vascular injury has emerged as a complication contributing to morbidity in coronavirus disease 2019 (COVID-19). The glycosaminoglycan hyaluronan (HA) is a major component of the glycocalyx, a protective layer of glycoconjugates that lines the vascular lumen and regulates key endothelial cell functions. During critical illness, as in the case of sepsis, enzymes degrade the glycocalyx, releasing fragments with pathologic activities into circulation and thereby exacerbating disease. Here, we analyzed levels of circulating glycosaminoglycans in 46 patients with COVID-19 ranging from moderate to severe clinical severity and measured activities of corresponding degradative enzymes. This report provides evidence that the glycocalyx becomes significantly damaged in patients with COVID-19 and corresponds with severity of disease. Circulating HA fragments and hyaluronidase, 2 signatures of glycocalyx injury, strongly associate with sequential organ failure assessment scores and with increased inflammatory cytokine levels in patients with COVID-19. Pulmonary microvascular endothelial cells exposed to COVID-19 milieu show dysregulated HA biosynthesis and degradation, leading to production of pathological HA fragments that are released into circulation. Finally, we show that HA fragments present at high levels in COVID-19 patient plasma can directly induce endothelial barrier dysfunction in a ROCK- and CD44-dependent manner, indicating a role for HA in the vascular pathology of COVID-19.

Background: Immunotherapy of gastrointestinal cancers is challenging; however, several lines of evidence suggest that adoptive transfer of stimulated or modified immune cells support not only protective role of immune cells in tumor microenvironment, but actively participate in the elimination of cancer cells. Methods: In vivo studies employing cancer cell-derived allograft murine models of gastrointestinal cancers were performed. The effects of T helper (Th) 2 cells on gastrointestinal cancers growth and tumor microenvironment composition using adoptive transfer of Th2 cells, interleukin (IL)-5 treatment, and immunofluorescence, multiplex and real-time PCR were explored. Results: Here, we show that Th2 cells play an essential role in the inhibition of colon and pancreas cancers progression. In murine models of gastrointestinal tumors using adoptive transfer of Th2 cells, we identify that Th2 cells are responsible for generation of apoptotic factors and affect macrophage as well as eosinophil recruitment into tumors where they produce cytotoxic factors. Moreover, we found that Th2 cells lead to IL-5 hypersecretion, which links the anti-tumorigenic function of Th2 cells and eosinophils. Importantly, we noted that recombinant IL-5 administration is also related with inhibition of gastrointestinal tumor growth. Finally, using an in vitro approach, we documented that both Th2 cells and eosinophils are directly responsible for gastrointestinal cancer cell killing. Conclusions: These data demonstrate the significance of Th2 cells, eosinophils and IL-5 in the inhibition of gastrointestinal tumor growth, and pointed toward tumor microenvironment reprogramming as a Th2 cell-mediated anti-tumorigenic mechanism of action.

The gastrointestinal (GI) mucosa is among the most complex systems in the body. It has a diverse commensal microbiome challenged continuously by food and microbial components while delivering essential nutrients and defending against pathogens. For these reasons, regulatory cells and receptors are likely to play a central role in maintaining the gut mucosal homeostasis. Recent lessons from cancer immunotherapy point out the critical role of the B7 negative co-stimulator PD-L1 in mucosal homeostasis. In this review, we summarize the current knowledge supporting the critical role of PD-L1 in gastrointestinal mucosal tolerance and how abnormalities in its expression and signaling contribute to gut inflammation and cancers. Abnormal expression of PD-L1 and/or the PD-1/PD-L1 signaling pathways have been observed in the pathology of the GI tract. We also discuss the current gap in our knowledge with regards to PD-L1 signaling in the GI tract under homeostasis and pathology. Finally, we summarize the current understanding of how this pathway is currently targeted to develop novel therapeutic approaches.

Tumor-associated macrophages (TAMs) in the gastrointestinal tumor microenvironment (TME) are known to polarize into populations exhibiting pro- or anti-tumoral activity in response to stimuli such as growth factors and cytokines. Our previous work has recognized granulocyte colony-stimulating factor (G-CSF) as a cytokine capable of influencing immune cells of the TME exhibiting pro-tumoral activity. Here, we aimed to focus on how G-CSF regulates TAM phenotype and function and the effects on gastrointestinal (GI) tumor progression. Thus, wildtype (WT) and G-CSFR^−/− macrophages were examined for cytokine production, gene expression, and transcription factor activity. Adoptive transfer of WT or G-CSFR^−/− macrophages into tumor-bearing mice was performed to study their influence in the progression of colon (MC38) and pancreatic (PK5L1940) tumor mouse models. Finally, the difference in cytotoxic potential between WT and G-CSFR^−/− macrophages was examined both in vitro and in vivo. Our results indicate that G-CSF promotes increased IL-10 production and decreased IL-12 production, which was reversed in G-CSFR^−/− macrophages for a pro-inflammatory phenotype. Furthermore, G-CSFR^−/− macrophages were characterized by higher levels of NOS2 expression and NO production, which led to greater tumor related cytotoxicity both in vitro and in vivo. Our results suggest that in the absence of G-CSFR, macrophage-related tumor cytotoxicity was amplified. These findings, along with our previous reports, pinpoint G-CSF /G-CSFR as a prominent target for possible clinical applications that aim to control the TME and the GI tumor progression.