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Analysis of Systemic Transport Barriers for the Activation of Anti‐tumor Immunity

Initiation of an immune response requires activation of one or more naïve T cells. Each naïve T cell has a unique T cell receptor, and these cells traffic through the blood and lymphatic vasculatures, visiting each of the ~500 lymph nodes in search of matching antigen. If a match is made, then the naïve T cell activates and proliferates. The resulting effector T cells enter the blood circulation to find and eradicate the source of antigen. Similar to pathogens like viruses, tumors can also create antigen that accumulates in local lymph nodes, where it can activate T cells. Unfortunately, even when this happens and the anti‐cancer effector cells find the tumor, they are prevented from killing by immune checkpoint programs that quench the immune response. In the past few years, multiple drugs have been approved that block these checkpoint programs, re‐enabling anti‐tumor immunity, and there have been miraculous cures in a subset of patients. However, there is an urgent need to understand why most patients (~85%) do not respond to these therapies. We explore the hypothesis that immune activation in these non‐responding patients is prevented or delayed due to transport limitations caused by the tumor that prevent colocalization of cognate naïve T cells and tumor antigen in the same lymph node. The model provides a mechanistic framework for optimizing cancer immunotherapy and developing testable solutions to unleash anti‐tumor immune responses for more patients with cancer.