# Surgery triggered immune response and liver metastases

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2024 · $387,041

## Abstract

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.

## Key facts

- **NIH application ID:** 10836338
- **Project number:** 5R01CA214865-08
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Allan Tsung
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $387,041
- **Award type:** 5
- **Project period:** 2018-01-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10836338

## Citation

> US National Institutes of Health, RePORTER application 10836338, Surgery triggered immune response and liver metastases (5R01CA214865-08). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10836338. Licensed CC0.

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