Emerging evidence indicate that cancer-associated fibroblasts (CAFs) affect tumor progression by reshaping the tumor microenvironment. Neutrophils are prominent components of solid tumors and important in cancer progression. Whether the phenotype and function of neutrophils in hepatocellular carcinoma (HCC) are influenced by CAFs is not well understood. Herein, we investigated the effect of HCC-derived CAFs (HCC-CAFs) on the neutrophils and explored the biological role of this effect. We found that HCC-CAFs induced chemotaxis of neutrophils and protected them from spontaneous apoptosis. Neutrophils were activated by the conditioned medium from HCC-CAFs with increased expression of CD66b, PDL1, IL8, TNFa, and CCL2, and with decreased expression of CD62L. HCC-CAF-primed neutrophils impaired T-cell function through the PD1/PDL1 signaling pathway. We revealed that HCC-CAFs induced the activation of STAT3 pathways in neutrophils, which are essential for the survival and function of activated neutrophils. In addition, we demonstrated that HCC-CAF-derived IL6 was responsible for the STAT3 activation of neutrophils. Collectively, our results suggest that HCC-CAFs regulate the survival, activation, and function of neutrophils within HCC through an IL6–STAT3–PDL1 signaling cascade, which presents a novel mechanism for the role of CAFs in remodeling the cancer niche and provides a potential target for HCC therapy.

BackgroundRegulatory B (Breg) cells represent one of the B cell subsets that infiltrate solid tumors and exhibit distinct phenotypes in different tumor microenvironments. However, the phenotype, function and clinical relevance of Breg cells in human hepatocellular carcinoma (HCC) are presently unknown.MethodsFlow cytometry analyses were performed to determine the levels, phenotypes and functions of TIM-1+Breg cells in samples from 51 patients with HCC. Kaplan-Meier plots for overall survival and disease-free survival were generated using the log-rank test. TIM-1+Breg cells and CD8+ T cells were isolated, stimulated and/or cultured in vitro for functional assays. Exosomes and B cells were isolated and cultured in vitro for TIM-1+Breg cell expansion assays.ResultsPatients with HCC showed a significantly higher TIM-1+Breg cell infiltration in their tumor tissue compared with the paired peritumoral tissue. The infiltrating TIM-1+Breg cells showed a CD5highCD24−CD27−/+CD38+/high phenotype, expressed high levels of the immunosuppressive cytokine IL-10 and exhibited strong suppressive activity against CD8+ T cells. B cells activated by tumor-derived exosomes strongly expressed TIM-1 protein and were equipped with suppressive activity against CD8+ T cells similar to TIM-1+Breg cells isolated from HCC tumor tissue. Moreover, the accumulation of TIM-1+Breg cells in tumors was associated with advanced disease stage, predicted early recurrence in HCC and reduced HCC patient survival. Exosome-derived HMGB1 activated B cells and promoted TIM-1+Breg cell expansion via the Toll like receptor (TLR) 2/4 and mitogen-activated protein kinase (MAPK) signaling pathways.ConclusionsOur results illuminate a novel mechanism of TIM-1+Breg cell-mediated immune escape in HCC and provide functional evidence for the use of these novel exosomal HMGB1-TLR2/4-MAPK pathways to prevent and to treat this immune tolerance feature of HCC.Electronic supplementary materialThe online version of this article (10.1186/s40425-018-0451-6) contains supplementary material, which is available to authorized users.

ReviewPolyinosinic-polycytidylic acid (polyi:c) is a synthetic analog of double-stranded RNA and an agonist of toll-like receptor (TLR) 3 and retinoic acid inducible gene i (RiG-i)-like receptors (RLRs), including RiG-i and melanoma differentiation-associated gene 5 (MDA5). The effect of polyi:c on tumor immunotherapy has been well explored for several decades. The accumulated evidence suggests that polyi:c could be used as a vaccine adjuvant to enhance innate and adaptive immune responses, and to alter the tumor microenvironment. Recent studies have also shown that activation of TLR3 and RLR signaling by polyi:c can directly trigger apoptosis in some cancer cells. This review focuses on polyi:c-induced signaling pathways and the applications of polyi:c in cancer treatment.

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Background: Oxidative stress and myocyte apoptosis are thought to play an important role in the pathogenesis, progression and prognosis of heart failure (HF). Heat shock protein 27 (Hsp27) has been found to confer resistance to oxidative stress in cultured cells; however, the role of Hsp27 in in-vivo hearts remains to be determined. Aim: To investigate the effects of Hsp27 over-expression on doxorubicin-induced HF. Methods and Results: Transgenic mice (TG) with cardiac specific over-expression of Hsp27 and their wild type littermates (WT) were challenged with doxorubicin (25 mg/kg, IP) to induce HF. At day 5, TG mice had significantly improved cardiac function and viability and decreased loss of heart weight following doxorubicin exposure compared with WT. In another parallel experiment, doxorubicin-induced increased levels of reactive oxygen species, protein carbonylation, apoptosis and morphologic changes were detected in the mitochondria in WT hearts, whereas these effects were markedly attenuated in TG hearts. In addition, upregulation of heat shock protein 70 and heme oxygenase-1 was present in the TG hearts after doxorubicin stimulation in comparison to WT hearts. Conclusion: These findings indicate that Hsp27 may play a key role in resistance to doxorubicin-induced cardiac dysfunction.