Systemic Modulation of Anti-Tumor Immunity Through Stromal Cell Reprogramming

Pengju Gong, MS (Advisor: Chunru Lin, PhD)

          Exercise has been associated with improved outcomes in patients with prostate cancer, but the mechanisms by which it remodels the tumor microenvironment remain poorly defined. Here, using the TRAMP spontaneous prostate cancer model, we show that mild treadmill exercise suppresses primary tumor growth, reduces metastatic burden, and prolongs survival. Single-cell RNA sequencing revealed that exercise reduced tumor epithelial representation while increasing immune and stromal compartments, with a marked shift from myofibroblasts toward fibroblasts and increased T-cell infiltration. Trajectory analysis supported a fibroblast-to-proto-myofibroblast-to-myofibroblast continuum that was altered by exercise. We identified ciliary neurotrophic factor (CNTF) as an exercise-associated circulating factor elevated in both exercising human donors and exercised mice. Its receptor, CNTFR, was reduced in prostate cancer relative to normal prostate tissue, whereas higher CNTFR expression was associated with favorable clinical outcome, reduced myofibroblast features, and increased CD8? T-cell infiltration. Mechanistically, tumor cells promoted myofibroblast differentiation through soluble factors, whereas recombinant CNTF (rCNTF) antagonized this tumor-induced stromal activation program in vitro. In vivo, rCNTF suppressed orthotopic tumor growth, reduced bone metastatic burden, and enhanced the efficacy of PD-1 blockade. These findings identify the CNTF-CNTFR axis as a mechanistic link between exercise and stromal-immune remodeling and support CNTF as a candidate exercise-mimetic strategy to enhance immunotherapy responsiveness in prostate cancer.

Advisory Committee:

• Chunru Lin, PhD, Chair
• Hussein Abbas, MD, PhD
• Leng Han, PhD
• Jian Hu, PhD
• Dung-Fang Lee, PhD
• Zhibin Zhang, PhD

Join via Zoom (Please contact Mr. Gong for his Zoom meeting info.)