Surgery triggered immune response and liver metastases

PROJECT SUMMARY Colorectal cancer is a devastating cause of mortality worldwide, with the majority of patients dying as a result of hepatic metastasis. When feasible, resection of hepatic metastases provides improved overall and disease-free survival; however, hepatic recurrence after surgical resection occurs in 50-60% of patients and is the major cause of treatment failure. Pre-operative exercise therapy (PEx), which has been shown to improve outcomes from major abdominal surgeries. It is known that exercise confers beneficial effects on the surgical outcome by regulating multiple mechanisms, including alteration of quantity and function of innate immune cells to provide an anti-inflammatory environment. Our recent findings demonstrate that PEx significantly attenuates liver surgery-induced hepatic inflammatory response (i.e., ischemia/reperfusion). PEx induces an anti-inflammatory phenotype in resident macrophages (Kupffer cells, KCs) causing distinct metabolic shifts by itaconate-mediated metabolic reprogramming. Our preliminary single-cell RNA-sequencing (scRNA-seq) data reveal that PEx causes dramatic transcriptomic changes not only in KCs but also in polymorphonuclear myeloid-derived suppressive cells (PMN-MDSCs) in the tumor microenvironment (TME). Furthermore, our preliminary data indicate that PEx significantly decreases PMN-MDSC from forming neutrophil extracellular traps (NETs), an important mechanism that links inflammation to nearly every stage in tumor progression. Given these findings, we hypothesize that that PEx ameliorates surgical stress-induced pro- tumorigenic inflammatory responses and sustains an anti-tumor immune microenvironment in the liver. In Aim 1, we will delineate the mechanisms of how PEx induces KC-mediated anti-tumor trained immunity. We will test the hypothesis that PEx induces an anti-tumor trained immunity in KCs via metabolic- epigenetic reprogramming, especially the itaconate/IRG1 pathway. In Aim 2, we will determine how PEx remodels the TME by suppressing PMN-MDSC formation of NETs to suppress hepatic metastatic tumor growth. In Aim 3, we will validate the effects of PEx on TME remodeling in patients undergoing liver surgery for metastatic colorectal cancer. Our proposal will delineate the molecular mechanisms of PEx in the regulation of immune cells in the TME of I/R-induced colorectal metastasis. The mechanisms discovered in these studies will provide the foundation for devising new exercise therapies that are mechanism-based and effective in improving surgical outcomes of cancer patients.