The Immunosuppressive Tumor Microenvironment and Mechanisms of Tumor Recurrence After Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS)

Background: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is considered to be a novel surgical treatment for patients with unresectable liver cancer. However, ALPPS has the high risk of early relapse. It is essential to explore the mechanisms underlying this early relapse after ALPPS.

Objective: We aim to depict the tumor microenvironment in ALPPS-treated tumor-bearing mice and explore the mechanisms of early relapse after ALPPS.

Methods: We devised a new ALPPS tumor-bearing mouse model to mimic clinical ALPPS. We used 10 post- ALPPS tumor-bearing mice and 10 untreated tumor-bearing mice for bulk RNA-seq and non-targeted metabolomic studies to explore the transcriptional signatures and metabolic characteristic of the liver and tumor tissues from ALPPS-treated tumor-bearing mice. Furthermore, we analyzed the tumor microenvironment of compared 6 paired normal and tumor tissues using single-cell RNA sequencing (scRNA-seq), . Additional in vitro and in vivo function assays were conducted to explore the role of Sdc1⁺ fibroblast and the mechanism of relapse after ALPPS.

Results: We found that there was infiltration of Cd4⁺ T_reg, Cd8⁺ T_ex and immunosuppressive macrophages in the tumor tissue of ALPPS-treated tumor-bearing mice, resulting in an immunosuppressive tumor microenvironment. We also identified a highly proliferative tumor subpopulation, and found that enriched Sdc1⁺ fibroblast regulated the proliferation, invasion and migration of this subpopulation via the Col1a2-Cd44 signaling axis, finally promoting tumor progression.

Conclusions: Both the identification and characterization of the immunosuppressive microenvironment and the mechanisms of tumor progression after ALPPS may be possible to develop a novel therapeutic strategy to reduce the risk of early recurrence.