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.
IntroductionRenal cell carcinoma accounts for 4% of all malignant tumors (1) and has an incidence of about 8-9 persons per 100,000 each year, which is increasing (2). There is no obvious symptom in the early stage of this cancer. As a result, approximately 25%-30% of patients exhibit tumor metastasis at first diagnosis and lose the opportunity for surgery (3). Although patients with primarily localized renal cell carcinoma can be successfully treated by partial or radical nephrectomy, one third of cases will subsequently develop metastases (4,5). Therapy of metastatic renal cell carcinoma is particularly difficult because of its poor response to radiotherapy or chemotherapy. Therefore, the prognosis for patients with metastatic renal cell carcinoma is poor, and the survival rate for 5 years is less than 10% (6). These lead to a rising demand for other treatment modalities.Prospective studies note spontaneous regression rates of up to 7% in patients with metastatic renal cell carcinoma (7,8). In addition, immunohistochemical studies of renal cell carcinoma often reveal tumor-infiltrating dendritic cells and T lymphocytes able to recognize and kill tumor cells (9). Therefore, renal cell carcinoma is considered an immunogenic tumor. These findings also lead to attempts to develop immunotherapeutic strategies using immunostimulatory cytokines such as interleukin-2 and interferon-α (10). It has been reported that treatment with interleukin-2 and interferon-α can induce antitumor activity in less than 20% of patients with metastatic renal cell carcinoma, but is associated with a high incidence Background/aim: Dendritic cell-based vaccine therapy for renal cell carcinoma is effective but requires improvement. Here we explored whether combination therapy with dendritic cell-based vaccine and anti-CD69 antibody can enhance antitumor efficacy in renal cell carcinoma-bearing mice.Materials and methods: Balb/c mice were challenged subcutaneously with murine renal cell carcinoma (Renca) cells. On day 3 after tumor cell inoculation, tumor-bearing mice either were left untreated or were treated with Renca tumor lysate-pulsed dendritic cells (i.e. dendritic cell-based vaccine), anti-CD69 antibody, or a combination of Renca tumor lysate-pulsed dendritic cells with anti-CD69 antibody. The mice were sacrificed on day 28. Tumor volume was measured for analysis of antitumor efficacy. Spleens were excised to evaluate antitumor immunological responses by measuring the proliferation and activation of T cells, which have the capacity to recognize and destroy tumor cells.Results: Combination treatment with Renca tumor lysate-pulsed dendritic cells and anti-CD69 antibody resulted in significant decreases in tumor volume and significant increases in T-cell proliferation and activity, compared with no treatment or either treatment alone. Conclusion:These findings indicate that anti-CD69 antibody can potentiate antitumor efficacy of dendritic cell-based vaccine. The augmented therapeutic efficacy conferred by the combination therapy may be as...
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