Abstract 683A: Mechanism of liver metastasis induced systemic suppression of checkpoint inhibitor response
Authors: Lee James C. , Daud Adil , Bluestone Jeff 
Published: July 2017

Abstract
Introduction: In stage IV melanoma and NSCLC, PD-1 checkpoint inhibitor therapy is effective and now FDA approved as first-line therapy. However, despite these rationally designed strategies to manipulate immune cells, curative responses remain rare, and the majority of metastatic cancer patients ultimately succumb to their disease. Emerging potential biomarkers of response have required specialized technologies such as next-generation sequencing or flow cytometry, which are difficult to access, costly, and not immediately clinically applicable. To this end, we have previously reported that presence of liver metastasis was significantly associated with the lack of antitumor immune infiltrates at distant biopsy sites as well as poor clinical response to PD-1 blockade. Here, we sought to study the mechanism of liver metastasis related non-response to PD-1 blockade using a syngeneic immunocompetent murine tumor model.
Methods: C57BL/6 mice were implanted with a "primary” subcutaneous tumor as well as a secondary “metastatic” tumor in the liver or the lungs (control), and given systemic PD-1 blockade therapy to mimic the clinical observation and study the effects of liver tumor involvement on systemic antitumor immunity. Animals are monitored for survival and tumor growth. The immune infiltrates of both the primary and metastatic sites are phenotypically analyzed.
Results: Animals with liver tumor involvement appear to have significantly shortened survival as well as difficulty rejecting tumors, both at the primary and secondary site of implantation, when compared to non-liver involved controls. The lack of response to PD-1 blockade in the liver cohort is correlated with a significant decrease in CTLA4+/PD-1+/CD8+ “exhausted” antigen experienced T cells (TEx) within the tumor microenvironment of the subcutaneous and liver-embedded sites. The deleterious effect on TEx appears to be liver-specific and not tumor cell-line dependent, as delivery of different tumor cells to the liver reproduces the same effect while delivery of tumor cells to other organs does not change the quantity of TEx at the subcutaneous site. Lastly, liver associated deletion of TEx appears to be a an antigen dependent process, as delivery of mismatched tumor cell line to the liver abrogates this effect and restores TEx within the tumor microenvironment at the distant subcutaneous site.
Conclusions: Using an immunocompetent checkpoint blockade animal tumor model, we recapitulated the clinically observed difference in response to PD-1 blockade treatment that is associated with liver metastasis. Our studies suggest that the liver is capable of suppressing effective T cell mediated antitumor response systemically, rendering checkpoint blockade less effective. The findings here propose a novel mechanism for which non-responsiveness to PD-1 blockade therapy could occur and may impact the treatment decision for cancer patients with liver metastasis.
Citation Format: James C. Lee, Adil Daud, Jeff Bluestone. Mechanism of liver metastasis induced systemic suppression of checkpoint inhibitor response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 683A. doi:10.1158/1538-7445.AM2017-683A