Vascular-targeting antiangiogenic therapy (VTAT) of cancer can be advantageous over conventional tumor cell targeted cancer therapy if an appropriate target is found. Our hypothesis is that endoglin (ENG; CD105) is an excellent target in VTAT. ENG is selectively expressed on vascular and lymphatic endothelium in tumors. This allows us to target both tumor-associated vasculature and lymphatic vessels to suppress tumor growth and metastasis. ENG is essential for angiogenesis/vascular development and a co-receptor of TGF-β. Our studies of selected anti-ENG monoclonal antibodies (mAbs) in several animal models and in vitro studies support our hypothesis. These mAbs and/or their immunoconjugates (immunotoxins and radioimmunoconjugates) induced regression of preformed tumors as well as inhibited formation of new tumors. In addition, they suppressed metastasis. Several mechanisms were involved in the suppressive activity of the naked (unconjugated) anti-ENG mAbs. These include direct growth suppression of proliferating endothelial cells, induction of apoptosis, ADCC (antibody-dependent cell-mediated cytotoxicity) and induction of T cell immunity. To facilitate clinical application, we generated a human/mouse chimeric anti-ENG mAb termed c-SN6j and performed studies of pharmacokinetics, toxicology and immunogenicity of c-SN6j in nonhuman primates. No significant toxicity was detected by several criteria and minimal immune response to the murine part of c-SN6j was detected after multiple i.v. injections. The results support our hypothesis that cSN6j can be safely administered in cancer patients. This hypothesis is supported by the ongoing phase 1 clinical trial of c-SN6j (also known as TRC105) in patients with advanced or metastatic solid cancer in collaboration with Tracon Pharma and several oncologists (NCT00582985).

Overcoming the immunosuppressive state in tumor microenvironments is a critical issue for improving the efficacy of cancer immunotherapy. Interleukin (IL)‐6, a pleiotropic cytokine, is highly produced in the tumor‐bearing host. Previous studies have indicated that IL‐6 suppresses the antigen presentation ability of dendritic cells (DC) through activation of signal transducer and activator of transcription 3 (STAT3). Thus, we focused on the precise effect of the IL‐6/STAT3 signaling cascade on human DC and the subsequent induction of antitumor T cell immune responses. Tumor‐infiltrating CD11b+ CD11c+ cells isolated from colorectal cancer tissues showed strong induction of the IL‐6 gene, downregulated surface expression of human leukocyte antigen (HLA)‐DR, and an attenuated T cell‐stimulating ability compared with those from peripheral blood mononuclear cells, suggesting that the tumor microenvironment suppresses antitumor effector cells. In vitro experiments revealed that IL‐6‐mediated STAT3 activation reduced surface expression of HLA‐DR on CD14+ monocyte‐derived DC. Moreover, we confirmed that cyclooxygenase 2, lysosome protease and arginase activities were involved in the IL‐6‐mediated downregulation of the surface expression levels of HLA class II on human DC. These findings suggest that IL‐6‐mediated STAT3 activation in the tumor microenvironment inhibits functional maturation of DC to activate effector T cells, blocking introduction of antitumor immunity in cancers. Therefore, we propose in this review that blockade of the IL‐6/STAT3 signaling pathway and target molecules in DC may be a promising strategy to improve the efficacy of immunotherapies for cancer patients.

Although MIF plays multifunctional roles in a broad spectrum of pathophysiological states, little has been done to investigate the role of this protein in association with tumor growth. The current results suggest the possibility that MIF induces tumor cell growth in concert with other growth factors, which encouraged us to investigate a novel approach for tumor therapy using an anti-MIF antibody and an MIF anti-sense plasmid transfection technique.

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Immunosuppression in tumor microenvironments critically affects the success of cancer immunotherapy. Here, we focused on the role of interleukin (IL)-6/signal transducer and activator of transcription (STAT3) signaling cascade in immune regulation by human dendritic cells (DCs). IL-6-conditioned monocyte-derived DCs (MoDCs) impaired the presenting ability of cancer-related antigens. Interferon (IFN)-γ production attenuated by CD4+ T cells co-cultured with IL-6-conditioned MoDCs corresponded with decreased DC IL-12p70 production. Human leukocyte antigen (HLA)-DR and CD86 expression was significantly reduced in CD11b+CD11c+ cells obtained from peripheral blood mononuclear cells (PBMCs) of healthy donors by IL-6 treatment and was STAT3 dependent. Arginase-1 (ARG1), lysosomal protease, cathepsin L (CTSL), and cyclooxygenase-2 (COX2) were involved in the reduction of surface HLA-DR expression. Gene expressions of ARG1, CTSL, COX2, and IL6 were higher in tumor-infiltrating CD11b+CD11c+ cells compared with PBMCs isolated from colorectal cancer patients. Expression of surface HLA-DR and CD86 on CD11b+CD11c+ cells was down-regulated, and T cell-stimulating ability was attenuated compared with PBMCs, suggesting that an immunosuppressive phenotype might be induced by IL-6, ARG1, CTSL, and COX2 in tumor sites of colorectal cancer patients. There was a relationship between HLA-DR expression levels in tumor tissues and the size of CD4+ T and CD8+ T cell compartments. Our findings indicate that IL-6 causes a dysfunction in human DCs that activates cancer antigen-specific Th cells, suggesting that blocking the IL-6/STAT3 signaling pathway might be a promising strategy to improve cancer immunotherapy