Immunological Insights Into Liver Metastasis Associated Resistance To Checkpoint Blockade Cancer Immunotherapy

Abstract Despite advancements in cancer immunotherapy, we have previously reported that stage IV melanoma and lung cancer patients with liver metastasis have decreased response rate to PD-1 blockade and shorter survival. A uniquely tolerogenic organ, the liver is the most common site of metastases of the majority of cancers, and cancer patients with liver metastasis have much worse survival overall. Thus, we hypothesized that cancer cells that metastasize to the liver may utilize liver-mediated tolerance mechanisms to decrease systemic anti-tumor immunity and render immunotherapies less effective. Metastatic melanoma patients with liver metastasis or other organ metastasis were biopsied pre and post PD-1 treatment and their distant primary site’s tumor immune infiltrates (TILs) were analyzed by FACS. Patients with liver metastasis had significantly lower CD8/Foxp3+ Treg ratio and decreased percentage of activated PD-1+/CTLA-4+ CD8 cells from their biopsy samples, suggesting a systemic influence on tumor immunity. To investigate the mechanism, C57BL/6 mice were implanted with “primary” subcutaneous (SQ) tumors and experimental “metastatic” tumors in the liver or control organ (lungs) and given systemic PD-1 blockade. Mice with liver metastasis had shortened survival and lower response rate to PD-1 blockade at the SQ site. TILs analysis within the SQ tumor of animals with liver metastasis shows lower CD8/Foxp3+ Treg ratio, lower expression of post-activation makers PD-1, CTLA-4, ICOS, and Ki67, and decreased tumor antigen tetramer-positive CD8 cells in a Treg dependent manner. These results indicate liver metastasis may induce systemic immune suppression to the detriment of stage IV cancer patients undergoing PD-1 blockade therapy.