Lymphatics: At the Interface of Immunity, Tolerance, and Tumor Metastasis

The lymphatic system has long been accepted as a passive escape route for metastasizing tumor cells. The classic view that lymphatics solely regulate fluid balance, lipid metabolism, and immune cell trafficking to the LN is now being challenged. Research in the field is entering a new phase with increasing evidence suggesting that lymphatics play an active role modulating inflammation, autoimmune disease, and the anti-tumor immune response. Evidence exists to suggest that the lymphatics and chemokines guide LN bi-functionally, driving immunity vs. tolerance according to demand. At sites of chronic inflammation, autoimmunity, and tumors, however, the same chemokines and aberrant lymphangiogenesis foster disease progression. These caveats point to the existence of a complex, finely balanced relationship between lymphatics and the immune system in health and disease. This review discusses emerging concepts in the fields of immunology, tumor biology, and lymphatic physiology, identifying critical, overlapping functions of lymphatics, the LN and lymphoid factors in tipping the balance of immunity vs. tolerance in favor of a growing tumor.