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 1 ) 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 1 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 1 B cells. More importantly, we provide evidence that CXCR31 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 1 B cells bridges proinflammatory interleukin-17 response and protumorigenic macrophage polarization in the tumor milieu, and blocking CXCR3 1 B-cell migration or function may help defeat HCC. (HEPATOLOGY 2015;62:1779-1790 T he communications between cancer cells and immune elements might directly promote tumor development and progression and/or result in immunoediting of tumors that fosters immune privilege and/or chronic inflammation.1-3 The subset composition and function of myeloid cells and T cells have been extensively studied in human cancers.4 B cells are essential components of humoral immunity and act as both antigen-presenting cells and effector cells, 5 but the subset composition and the biological role of B cells are poorly defined in the human cancer microenvironment.As the clinical application of monoclonal antibodies increases, the antitumor effect of antigen-specific B cells receives increasing attention.6 Antibodies secreted byAbbreviations: B-cell-CM, 25% conditioned medium from tumor CXCR3 1 B

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We identified a novel protumorigenic IL21 T-like cell subset with a CXCR5PD-1 BTLACD69 tissue-resident phenotype in hepatoma. TLR4-mediated monocyte inflammation and subsequent T-cell STAT1 and STAT3 activation are critical for T-like cell induction. T-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 constitute abundant cellular components in inflamed human tissues, but their role in pathogenesis of inflammatory T helper (TH) subsets is still unclear. Here, we demonstrate that B cells, particularly resting naïve B cells, have a previously unrecognized helper function that is involved in shaping the metabolic process and subsequent inflammatory differentiation of T-cell receptor–primed TH cells. ICOS/ICOSL axis–mediated glucose incorporation and utilization were crucial for inflammatory TH subset induction by B cells, and activation of mTOR was critical for T cell glycolysis in this process. Consistently, upon encountering ICOSL+ B cells, activated effector memory TH cells from patients with rheumatoid arthritis or systemic lupus erythematosus spontaneously differentiated into inflammatory TH subsets. Immunotherapy using rituximab that specifically depleted B cells in patients with rheumatoid arthritis efficiently abrogated the capabilities of memory TH cells to incorporate and use glucose, thereby impairing the pathogenic differentiation of inflammatory TH subsets.

<p>Supplementary Table S2. Clinical Characteristics of the 293 HCC Patients. Supplementary Table S3. Clinical Characteristics of the 16 Gastric Cancer Patients. Supplementary Table S4. Relationships between Peritumoral Stromal IL-21+ Cells and Clinicopathological Characteristics. Supplementary Table S5. Univariate and Multivariate Analyses of Factors Associated with Survival and Recurrence. Supplementary Table S6. Antibodies for Immunoblotting. Supplementary Table S7. Fluorochrome-Conjugated Antibodies Used in Flow Cytometry. Supplementary Table S8. Primers for Real-Time PCR.</p>

<p>Supplementary Table S1. Characteristics of Patients Contributing Samples in Figures 1, 2, 4 and 5.</p>

<p>Supplementary Table S1. Characteristics of Patients Contributing Samples in Figures 1, 2, 4 and 5.</p>

<p>Supplementary Figure S1. Identification of IL-21 + Tissue-Resident T FH -Like Cells in Human HCC. Supplementary Figure S2. Monocytes/Mφ Polarize IL-21 + T FH -Like Cells in Cancer Microenvironments. Supplementary Figure S3. Innate Monocyte Activation Is Essential for IL-21 + T FH -Like Cell Differentiation. Supplementary Figure S4. Effects of Inflammatory Cytokines on STAT1 and STAT3 Activation. Supplementary Figure S5. High Density of IL-21 + T FH -like Cells Predicts Poor Survival of HCC Patients and Induces M2b Mφ Polarization. Supplementary Figure S6. Efficiency of IgG Depletion by Protein G. Supplementary Figure S7. Summary of Results.</p>