Transarterial embolization modulates the immune response within target and non-target hepatocellular carcinomas

Recent successes in the field of immuno-oncology have generated considerable interest in the investigation of approaches that combine standard of care treatments with immunotherapies. Transarterial embolization (TAE) represents an attractive candidate for this approach given the potential for immune system stimulation, however little is known about the influence of TAE on the tumor immunoenvironment. The purpose of this study was to perform a cellular analysis of tumor infiltrating lymphocytes (TILs) and PD-L1 expression following TAE in a translational rat model of hepatocellular carcinoma (HCC) and to identify factors that influence this response. We show that TAE causes dynamic changes in immune cell populations, with variable increases in CD3, CD4, and CD8 cells within embolized tumors over time. We also show that TAE alters the immunobiology of distant, non-target tumors as demonstrated by an increased number of CD4, CD8, and Foxp3+ cells within the intratumoral compartment of non-target tumors. We demonstrate that, in response to TAE, tumor cells up-regulate expression of PD-L1. Finally, we demonstrate marked differences in terms of the foreign body reactions induced by two commonly used embolic particles, and show changes in lymphocyte and macrophage recruitment that depend on the type of embolic particles and their propensity to extravasate beyond the vasculature and into the tumor parenchyma. These findings hold important implications for the on-going development of novel therapeutic strategies combining locoregional therapy with immunomodulators, as well as for the development of techniques and materials that can further leverage the unique modulation of the tumor immune microenvironment.