Immune interconnectivity of anatomically distant tumors as a potential mediator of systemic responses to local therapy.

Complex interactions occur between tumor and host immune system at each site in the metastatic setting, the outcome of which can determine behavior ranging from dormancy to rapid growth. An additional layer of complexity arises from the understanding that cytotoxic T cells can traffic through the host circulatory system. Coupling mathematical models of local tumor-immune dynamics and systemic T cell trafficking allows us to simulate the evolution of tumor and immune cell populations in anatomically distant sites following local therapy and thus computationally evaluate immune interconnectivity. Results suggest that the presence of a secondary site may either inhibit or promote growth of the primary, depending on the capacity for immune recruitment of each tumor and the resulting systemic redistribution of T cells. Treatment such as surgical resection and radiotherapy can be simulated to estimate both the decrease in tumor volume at the local treatment-targeted site, and the change in overall tumor burden and tumor growth trajectories across all sites. Qualitatively similar responses of distant tumors to local therapy (positive and negative abscopal effects) to those reported in the clinical setting were observed. Such findings may facilitate an improved understanding of general disease kinetics in the metastatic setting: if metastatic sites are interconnected through the immune system, truly local therapy does not exist.