53: Preoperative exercise therapy attenuates surgical stress induced liver metastases by inducing Kupffer cell-mediated anti-tumor immunity

Saturday, March 23, 2024

8:32am – 8:42am ET

Location: C105-106

Abstract Presenter(s)

Susan J. Kim, MD (she/her/hers)

Post-doctoral Research Fellow
University of Virginia
Charlottesville, Virginia, United States

Submitter(s)

Susan J. Kim, MD (she/her/hers)

Post-doctoral Research Fellow
University of Virginia
Charlottesville, Virginia, United States

Author(s)

Susan J. Kim, MD (she/her/hers)

Post-doctoral Research Fellow
University of Virginia
Charlottesville, Virginia, United States
CS

Chengli Shen, MS, PhD

Research Scientist
University of Virginia, United States
YZ

Yunwei Zhang, MD PhD

Post-Doctoral Research Associate
University of Virginia, United States
HZ

Hongji Zhang, Md PhD

Assistant Professor
University of Virginia, United States
Allan Tsung, MD

Chair of Department of Surgery, Professor of Surgery, Principal Investigator
University of Virginia, United States

Disclosure(s):

Susan J. Kim, MD: No financial relationships to disclose

Introduction: Resection of hepatic metastases from colorectal cancer enhances overall disease-free survival. However, not every patient achieves a favorable surgical outcome. Pre-operative exercise therapy (PEx) has shown potential in mitigating adverse post-operative outcomes. Our hypothesis is that PEx, at the outset, counters pro-tumorigenic inflammatory responses induced by surgical stress and subsequently preserves an anti-tumor immune microenvironment.

Methods: 8 weeks-old male C57BL/6 mice were randomly divided into PEx and sedentary (Sed) groups. Mice in PEx group ran on a motorized treadmill at a speed of 12.5 m/min for 60 min/day, 5 days/week, for 4 weeks. 1 x 10⁵ GFP-labeled MC38 colon cancer cells were injected directly through the portal vein and surgical stress was subjected through a 70% hepatic ischemia and reperfusion (I/R) model. Tumor growth was measured by in vivo bioluminescent imaging weekly, and the gross tumor nodules were counted upon mouse sacrifice 3 weeks after index surgery. Tumor CD45+ cells from PEx or Sed mice 3 weeks after I/R were submitted for single-cell RNA sequencing (scRNA-seq) and flow cytometry.

Results: 4 weeks of PEx significantly reduced hepatic metastases 3 weeks after surgery, compared with Sed controls. 11 cell lineages were identified and annotated according to the transcriptomic profile of feature genes expression via scRNA-seq. Surprisingly, 4-weeks-PEx led to a significant transcriptomic shift in Kupffer cells (KC). 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. Flow cytometry verified that PEx-relevant KCs secreted more IFN-γ and TNF-α which play a tumor killing function.

Conclusions: Our research is among the pioneering studies to demonstrate that PEx prompts a transition in KCs towards a tumoricidal phenotype. This discovery provides a compelling argument for the utilization of PEx in cancer patients undergoing liver surgery, with the potential to reduce post-operative metastasis.

Learning Objectives:

Upon completion, participant will be able to define pre-operative exercise therapy and its proposed effect on the tumor microenvironment.
Upon completion, participant will be able to describe the functional change between pre-operative exercise therapy relevant Kupffer cells and sedentary relevant Kupffer cells.
Upon completion, participant will be able to hypothesize plausible biologic causes for post-operative metastases in sedentary models.