Macrophages and dendritic cells play an important role in regulating B-cell responses, including proliferation to antigens such as trinitrophenyl (TNP)—Ficoll and TNP-Brucella abortus. However, the mechanisms and molecule(s) that regulate these processes are relatively undefined. In this report, we show that human macrophages generated in vitro strongly costimulate proliferation of dense human tonsillar B cells ligated via their B-cell antigen receptor (BCR) but not proliferation via CD40. Similarly, dendritic cells also markedly enhance BCR-activated B-cell proliferation. Soluble molecule(s) are required for human macrophages to costimulate proliferation of B cells triggered via their BCR. Importantly, a TACI (trans-membrane activator and CAML interactor)—Fc fusion protein inhibits both macrophage- and dendritic cell (DC)—dependent BCR-activated B-cell proliferation, indicating a requirement for at least one of the known TACI ligands, BAFF and/or APRIL. Consistent with a major role for BAFF, macrophages release BAFF at levels sufficient to potently costimulate BCR-induced B-cell proliferation. In addition, BAFF is more than 100-fold more potent than APRIL in enhancing BCR-mediated human B-cell proliferation. Furthermore, immunodepletion of APRIL under conditions that prevent APRIL-mediated B-cell costimulation does not block macrophage enhancement of B-cell proliferation. Finally, there is no correlation between the high levels of a proliferation-inducing ligand (APRIL) expressed by macrophages compared with DCs and the similar abilities of macrophages and DCs to enhance BCR-stimulated B-cell proliferation. In summary, our results suggest that macrophage- and DC-derived B-cell—activating factor belonging to the TNF family (BAFF) represents a key molecule by which macrophages and DCs directly regulate human B-cell proliferative responses to T-cell—independent stimuli.

Sarcopenia is associated with increased morbidity and mortality in oncologic and transplant surgery. It has a high incidence in chronic inflammatory states including inflammatory bowel disease (IBD). The validity of existing data in IBD and of sarcopenia’s correlation with surgical outcomes is limited. We performed a systematic review to assess the correlation of sarcopenia with the requirement for surgery and surgical outcomes in patients with IBD. Observational studies of patients with IBD in whom an assessment of sarcopenic status/skeletal muscle index was undertaken, a proportion of whom proceeded to surgical management, were selected. A total of 5 studies with a combined 658 IBD patients met the inclusion criteria. The majority (70%) had a diagnosis of Crohn’s disease. Median (range) body mass index and skeletal muscle index were reported in 4 studies and were 16.58 (13.66–22.50) kg/m² and 44.52 (42.90–50.64) cm²/m², respectively. Forty-two percent of IBD patients had sarcopenia. Notably, none of the studies assessed both the anatomical and functional component required for a correct assessment of sarcopenia. Three studies noted that sarcopenic IBD patients had a higher probability of requiring surgery. The rate of major complications (Clavien-Dindo grade ≥IIIa) was significantly higher in patients with sarcopenia. Improved perioperative nutrition management may mitigate the risk of complications. Many IBD patients are young, may be malnourished, and commonly require emergent surgery. There is considerable heterogeneity in the assessment of sarcopenia. Sarcopenia is common in the IBD population and can predict the need for surgical intervention. Sarcopenia correlates with an increased rate of major postoperative complications. Improved perioperative intervention may diminish this risk. A formal assessment, screening by a dedicated IBD dietician, and preoperative physical therapy may facilitate early intervention.

Chemotherapy-induced diarrhea (CID) is a common and often severe side effect experienced by colorectal cancer (CRC) patients during their treatment. As chemotherapy regimens evolve to include more efficacious agents, CID is increasingly becoming a major cause of dose limiting toxicity and merits further investigation. Inflammation is a key factor behind gastrointestinal (GI) toxicity of chemotherapy. Different chemotherapeutic agents activate a diverse range of pro-inflammatory pathways culminating in distinct histopathological changes in the small intestine and colonic mucosa. Here we review the current understanding of the mechanisms behind GI toxicity and the mucositis associated with systemic treatment of CRC. Insights into the inflammatory response activated during this process gained from various models of GI toxicity are discussed. The inflammatory processes contributing to the GI toxicity of chemotherapeutic agents are increasingly being recognised as having an important role in the development of anti-tumor immunity, thus conferring added benefit against tumor recurrence and improving patient survival. We review the basic mechanisms involved in the promotion of immunogenic cell death and its relevance in the treatment of colorectal cancer. Finally, the impact of CID on patient outcomes and therapeutic strategies to prevent or minimise the effect of GI toxicity and mucositis are discussed.

Our current understanding of human tumor resident myeloid cells is, for the most part, based on a large body of work in murine models or studies enumerating myeloid cells in patient tumor samples using immunohistochemistry (IHC). This has led to the establishment of the theory that, by and large, tumor resident myeloid cells are either ‘pro-tumor’ M2 macrophages or myeloid derived suppressor cells (MDSC). This concept has accelerated our understanding of myeloid cells in tumor progression and enabled the elucidation of many key regulatory mechanisms involved in cell recruitment, polarization and activation. On the other hand, this paradigm does not embrace the complexity of the tumor resident myeloid cell phenotype (IHC can only measure 1 or 2 markers per sample) and their possible divergent function in the hostile tumor microenvironment (TME). Here we examine the criteria that define human tumor infiltrating myeloid cell subsets and provide a comprehensive and critical review of human myeloid cell nomenclature in cancer. We also highlight new evidence characterizing their contribution to cancer pathogenesis based on evidence derived from clinical studies drawing comparisons with murine studies where necessary. We then review the mechanisms in which myeloid cells are regulated by tumors in humans. We then review the mechanisms in which myeloid cells are regulated by tumors in humans and how these are being targeted therapeutically.

Upon binding their cognate receptors, ERα (ESR1) and ERβ (ESR2), estrogens activate intracellular signaling cascades that have important consequences for cellular behavior. Historically linked to carcinogenesis in reproductive organs, estrogens have also been implicated in the pathogenesis of different cancer types of non-reproductive tissues including the colon. ERβ is the predominant estrogen receptor expressed in both normal and malignant colonic epithelium. However, during colon cancer progression ERβ expression is lost, suggesting estrogen signaling may play a role in disease progression. Estrogens may in fact exert an anti-tumor effect through selective activation of pro-apoptotic signaling mediated by ERβ, inhibition of inflammatory signals and modulation of the tumor microenvironment. In this review we analyze the estrogen pathway as a possible therapeutic avenue in colorectal cancer, we report the most recent experimental evidence to explain the cellular and molecular mechanisms of estrogen-mediated protection against colorectal tumorigenesis, and we discuss future challenges and potential avenues for targeted therapy.

Background: Natural killer (NK) cells may be impaired in patients with persistent hepatitis C virus (HCV) infection, but studies to date have yielded inconsistent findings due to patient and virus heterogeneity and difficulties obtaining appropriate controls. Aims: To overcome these variables, we have examined numbers, phenotypes, cytotoxic activities and cytokine profiles of circulating NK cells from Irish women who acquired infection through administration of HCV genotype 1b-contaminated anti-D immunoglobulin from a single source and matched controls. Results: Comparing 29 women who developed persistent infection with 21 who spontaneously resolved infection and 26 controls, we found that NK cell numbers were consistently lower in the persistently infected group (p = 0.02 and 0.002). This decrease was due to depletions of NK cells expressing low levels of CD56 (CD56^dim NK cells; p = 0.004 and 0.0001), whilst CD56^bright NK cells were expanded (p = 0.004 and 0.0001). Compared to HCV resolvers, CD56^dim NK cells from persistently infected patients less frequently expressed CD16 and more frequently expressed NKG2A/C/E. These phenotypic changes did not significantly affect natural or interleukin-2-induced cytotoxicity by peripheral blood mononuclear cells against K562 and Daudi targets. Greater frequencies of CD56^bright NK cells from chronic HCV patients produced interferon-γ compared with HCV responders (p = 0.05) and controls (p = 0.0001) after phorbol ester stimulation in vitro. Conclusions: Alterations in NK subset distributions in chronic HCV infection may explain why previous reports of impaired NK cell functions were difficult to confirm. Altered NK cell functions may contribute to impaired cellular immune responses and chronicity of disease following HCV infection.