Deciphering the Hepatic Pre-Metastatic Microenvironment

Recent work in animal models suggests that the hepatic immune microenvironment governs early metastatic progression, primarily through T cell-mediated pruning of occult cancer cells as they progress from a quiescent to a proliferative state. This transition is characterized by re-expression of MHC class I (MCHI), which is suppressed during dissemination and initial metastatic seeding, thus representing a pro-growth phenotypic switch that also permits detection by adaptive immunity. Existing models therefore posit that dormant, MHCI- cancer cells reside ubiquitously within patient livers until proliferative capacity is restored, at which point eradication or progression depends on the strength of an active T cell response. Confirmatory studies in human patients, however, have been lacking, due to the exclusion of “normal” liver tissue from biobanking programs, and the technical hurdles of cell-type-specific, multi-dimensional analyses required to probe these interactions

Leveraging our unique biobanking program, we have developed an experimental pipeline in collaboration with the Crosby Laboratory to profile hepatic immunity with exquisite precision. We have confirmed that our liver biopsies reflect the entire hepatic immune microenvironment with high fidelity, and preliminary data from these efforts demonstrate that 1) the liver houses unique innate immune populations potentially capable of targeting cells that suppress self MHC, and 2) immunosuppressive populations known to blunt adaptive immunity in primary tumors also reside within the hepatic premetastatic microenvironment. Based on these findings, we are now approaching whether dormant MHCI- cancer cells are, in fact, initially vulnerable to hepatic innate immunity, and if T cell-mediated elimination of MHCI+ cells is ultimately compromised by tumor-associated immunosuppressive signals, permitting metastatic escape.