Surgical stress promotes development of colorectal liver metastases via modulation of hepatic regulatory T cells 4216

Abstract Description Background Surgery is central to treatment of colorectal liver metastases (CRLM), yet up to 75% of patients recur. A proposed driver is the reshaping of the hepatic immune microenvironment (IME) during surgical stress [ischemia/reperfusion injury (IRI)]. Regulatory T cells (Tregs) promote repair of injured tissues but are also immunosuppressive during tumorigenesis. We hypothesize that Tregs increase in the liver after IRI and foster an IME conducive to development of LM. Methods MC38-luciferase cells were injected after hepatic IR. Tregs were depleted with CD25 antibody in C57BL/6 mice; diphtheria toxin in FoxP3-DTR mice. Tumor growth was quantified by bioluminescence, liver-to-body weight, and macroscopic nodules. Hepatic IME was assessed by flow cytometry (%Foxp3+/CD4+). scRNA-seq identified transcriptomic changes in Tregs from IR vs. sham (SH) livers. Results Increased hepatic Tregs were demonstrated 1 week after IR. Hepatic IR increased Tregs in liver and circulation in tumor bearing mice. In Treg-depleted mice, liver IR-augmented tumor growth was abrogated 2 weeks after surgery. Top differentially expressed genes in IR Tregs were implicated in metastasis: S100a9, S100a8, Cxcl2, Tnfaip3, Ctla4. Strong cell-cell interaction between Tregs and monocytes was observed by Cellchat analysis. Summary: Hepatic IRI boosts infiltration of Tregs with a pro-tumorigenic phenotype, promoting CRLM. Depletion of Tregs before IR and during tumor development hinders this process. Funding Sources Supported by R01GM137203 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)