Lymphangiogenesis and anti-tumor immune responses.

Tumor-induced immunosuppression is a fundamental problem in cancer immunotherapy and can occur by a variety of cellular and molecular mechanisms, affecting all arms of the immune system. Tumor-produced or elicited factors have been shown to inhibit antigen-specific immune effector function as well as impairment of the development, recruitment and maturation of dendritic cells (DCs) and T cells. A better understanding of the cross-talk between tumors and tumor-associated DCs and T cells is necessary to develop novel approaches for cancer immunotherapy. The recruitment of DCs to tumors, antigen processing and presentation, and migration of antigen-loaded DCs to secondary lymphoid organs are perturbed in tumor-bearing hosts. The ability of tumor-associated DCs to induce an anti-tumor response may be prevented by the tumor microenvironment due to inhibitory factors such as vascular endothelial growth factor (VEGF)-C, which are also known to regulate tumor angiogenesis and lymphangiogenesis. Strategies to inhibit tumor-induced angiogenesis and immunosuppression provide therapeutic approaches with the potential for synergism. In this review we will discuss the possibilities of developing novel approaches to concurrently inhibit angiogenesis, inhibit lymphangiogenesis, eliminate tumor-induced immunosuppression and augment the anti-tumor immune as potent multi-modality therapeutic strategies for metastatic cancer.