B cell regulation of the anti-tumor response and role in carcinogenesis

The balance between immune effector cells such as T cells and natural killer cells, and immunosuppressive Treg cells, dendritic, myeloid and monocytic sub-populations in the tumor microenvironment acts to calibrate the immune response to malignant cells. Accumulating evidence is pointing to a role for B cells in modulating the immune response to both solid tumors and hematologic cancer. Evidence from murine autoimmune models has defined B regulatory cell (Breg) subsets that express cytokines such as IL-10, TGF-β, and/or express immune regulatory ligands such as PD-L1, which can suppress T cell and/or natural killer cell responses. Multiple murine tumor models exhibit decreased tumor growth in B cell deficient or B cell depleted mice. In several of these models, B cells inhibit T cell mediated tumor immunity and/or facilitate conversion of T cells to CD4(+)CD25(+)FoxP3(+) T regs, which act to attenuate the innate and/or adaptive antitumor immune response. Mechanisms of suppression include the acquisition of inhibitory ligand expression, and phosphorylation of Stat3, and induction of IL-10 and TGF-β, resulting in a Breg phenotype. Breg suppressive activity may affect diverse cell subtypes, including T effector cells, NK cells, myeloid derived suppressor cells (MDSC) and/or tumor associated macrophages. B cells may also directly promote tumorigenesis through recruitment of inflammatory cells, and upregulation of pro-angiogenic genes and pro-metastatic collagenases. Breg infiltration has now been identified in a variety of solid tumor malignancies including but not limited to ovarian, gastric, non-small cell lung cancer, pancreatic, esophageal, head and neck, and hepatocellular carcinomas. Increasing evidence suggests that recruitment of B cells and acquisition of suppressive activity within the tumor bed may be an important mechanism through which B cells may modulate innate and/or adaptive anti-tumor immunity. B cell depletion in the clinic using anti-CD20 antibodies and/or inhibitors of BTK and/or other signaling pathways, may be a useful strategy for augmenting the anti-tumor immune response

Plasma Indoleamine 2,3-Dioxygenase Concentration is Increased in Hemodialysis Patients and May Contribute to the Pathogenesis of Coronary Heart Disease

Introduction: Coronary heart disease (CHD) is the leading cause of death in hemodialysis (HD) patients. Inflammation contributes to the pathogenesis of atherosclerosis in this population. Indoleamine 2,3-dioxygenase (IDO), an enzyme with immunomodulatory properties, was evaluated in HD patients with or without CHD. Methods: Of the total of 66 HD patients, 22 of them with CHD were confirmed by coronary angiography and 24 healthy volunteers were enrolled in the study. Plasma IDO was assessed by means of enzyme-linked immunosorbent assay. Serum interleukin-6 (IL-6) and C-reactive protein (CRP) were also measured. Results: Compared with healthy volunteers, plasma IDO concentration was markedly increased in HD patients (median 8.04 ng/mL vs. 48.9 ng/mL). Serum IL-6 and CRP were also significantly increased in HD patients. Compared with HD patients without CHD, plasma IDO concentration was significantly increased in HD patients with CHD (median 38.6 ng/mL vs. 74.5 ng/mL). Neither IL-6 nor CRP differed between the last two groups. IDO was negatively correlated with IL-6 and CRP. Conclusion: IDO concentration is increased in HD patients and is increased further in HD patients with CHD. It remains to be elucidated if increased IDO plays a direct role in the pathogenesis of atherosclerosis or if it affects atherosclerosis indirectly by curtailing chronic inflammation or both