Qiu‐Hui Zeng

UNLABELLED: B cells consistently represent abundant cellular components in tumors; however, direct evidence supporting a role for B cells in the immunopathogenesis of human cancers is lacking, as is specific knowledge of their trafficking mechanisms. Here, we demonstrate that chemokine (C-X-C motif) receptor 3-positive (CXCR3(+)) B cells constitute approximately 45% of B-cell infiltrate in human hepatocellular carcinoma (HCC) and that their levels are positively correlated with early recurrence of HCC. These cells selectively accumulate at the invading edge of HCC and undergo further somatic hypermutation and immunoglobulin G-secreting plasma cell differentiation. Proinflammatory interleukin-17(+) cells are important for the induction of epithelial cell-derived CXCR3 ligands CXCL9, CXCL10, and CXCL11, which subsequently promote the sequential recruitment and further maturation of CXCR3(+) B cells. More importantly, we provide evidence that CXCR3(+) B cells, but not their CXCR3(-) counterparts, may operate in immunoglobulin G-dependent pathways to induce M2b macrophage polarization in human HCC. Depletion of B cells significantly suppresses M2b polarization and the protumorigenic activity of tumor-associated macrophages and restores the production of antitumorigenic interleukin-12 by those cells in vivo. CONCLUSION: Selective recruitment of CXCR3(+) B cells bridges proinflammatory interleukin-17 response and protumorigenic macrophage polarization in the tumor milieu, and blocking CXCR3(+) B-cell migration or function may help defeat HCC.

Abstract The existence, regulation, and functions of IL21+ immune cells are poorly defined in human cancers. Here, we identified a subset of protumorigenic IL21+ TFH-like cells in human hepatocellular carcinoma. These cells were the major source of IL21 in tumors and represented about 10% of the CD4+ T-cell population at levels comparable with the TFH cells present in lymph nodes. However, these TFH-like cells displayed a unique CXCR5−PD-1lo/−BTLA−CD69hi tissue-resident phenotype with substantial IFNγ production, which differed from the phenotype of TFH cells. Toll-like receptor 4 (TLR4)–elicited innate monocyte inflammation was important for IL21+ TFH-like cell induction in tumors, and activation of STAT1 and STAT3 was critical for TFH-like cell polarization in this process. Importantly, the TFH-like cells operated in IL21–IFNγ-dependent pathways to induce plasma cell differentiation and thereby create conditions for protumorigenic M2b macrophage polarization and cancer progression. Thus, induction of TFH-like cells links innate inflammation to immune privilege in tumors. Significance: We identified a novel protumorigenic IL21+ TFH-like cell subset with a CXCR5−PD-1− BTLA−CD69hi tissue-resident phenotype in hepatoma. TLR4-mediated monocyte inflammation and subsequent T-cell STAT1 and STAT3 activation are critical for TFH-like cell induction. TFH-like cells operate via IL21–IFNγ pathways to induce plasma cells and create conditions for M2b macrophage polarization. Cancer Discov; 6(10); 1182–95. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 1069

B cells have a previously unrecognized helper function in triggering pathogenic differentiation of inflammatory T H subsets.

Effects of guanidinoacetic acid (GAA) supplementation in all-plant protein diets were evaluated on growth, antioxidant capacity and muscle energy metabolism of Rana (Lithobates) catesbeiana. Six diets were prepared: a basal fish meal diet (FM), an all soybean meal diet (SM) and four GAA-supplemented diets by adding 0.2, 0.4, 0.6 and 0.8 g GAA/kg to the SM diet (GAA2, GAA4, GAA6 and GAA8 diets). Triplicate groups of bullfrog (45 ± 0.2 g) were fed the diets to apparent satiation for 8 weeks. Total substitution of FM with SM led to significantly (p < .05) reduced growth and feed utilization. Adding 0.4 g GAA/kg to the SM diet significantly improved growth performance, and the values were comparable to those of FM group. SM and GAA2 groups showed drastically lower serum total antioxidant capacity than FM, GAA4 and GAA6 groups. Also, SM and GAA2 groups showed significantly lower catalase activity than FM and GAA8 groups. A remarkable increase in serum malondialdehyde concentration was detected in SM and GAA2 groups. FM and GAA6 groups exhibited significantly higher serum creatinine concentration than other groups. Muscle creatine kinase activity and glycogen content were significantly decreased in SM group and application of 0.4–0.6 g GAA/kg significantly improved their values. GAA4 group showed significantly lower pyruvate kinase activity than FM and GAA6 groups. Also, GAA2 and GAA4 groups had significantly lower succinate dehydrogenase (SDH) activity than other treatments. These findings show that supplementing 0.4 g/kg GAA to SM-based diets improves growth, antioxidant capacity and muscle energy metabolism.