Preoperative exercise therapy attenuates liver metastases following surgical stress by inducing Kupffer cells-mediated anti-tumor immunity

Abstract

Abstract Introduction Resection of colorectal cancer hepatic metastases improves overall disease-free survival. Unfortunately, not all patients have a successful surgical outcome. Pre-operative exercise therapy (PEx) have been demonstrated to be beneficial in the prevention of post-operative complications. We hypothesize that PEx initially reverts pro-tumorigenic inflammatory responses following surgical stress and maintains an anti-tumor immune microenvironment through modulating Kupffer cells (KCs) with anti-tumor immunity. Methods 8W C57BL/6 mice were randomly divided into PEx and sedentary (Sed) groups, mice with PEx run on a motorized treadmill at a speed of 12.5 m/min for 60 min/day, 5 days/W for 4 weeks. 105 MC38 cells were injected directly through portal vein and surgical stress was subjected to partial hepatic ischemia and reperfusion model. Both hepatic and tumor CD45+ cells from PEx or Sed mice 3 W after IR were submitted for single-cell RNA sequencing (scRNA-seq). Results 4 weeks of PEx significantly reduces metastasis in the liver along 3 weeks after IR, compared with Sed controls. For the scRNA-seq, 11 cell lineages were identified and annotated according to the transcriptomic profile of feature genes expression. Surprisingly, discontinued 4-week-PEx still led to a significant transcriptomic shift in the KCs. 3 clusters from the entire KCs population were unique in PEx mice. In contrast, 2 Clusters were derived from Sed mice. PEx-relevant KCs are enriched in gene expression related to the anti-tumor phenotype, whereas Sed-relevant KCs are enriched in gene expression related to pro-tumor or immunosuppressive phenotype, which suggests that PEx modulates transcriptomic changes in KCs towards an anti-tumor phenotype. Supported by National Institutes of Health R01-CA214865-01 and R01-GM95566-06 to AT, National Institutes of Health R01-AI152044 to MD, and National Institutes of Health R01-GM137203 and Joseph A. Patrick Research Fellowship in Transplantation to HH.