Dissertations and Theses (Open Access)

Author ORCID Identifier

https://orcid.org/0000-0002-8168-7187

Date of Graduation

8-2026

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Chunru Lin, Ph.D.

Committee Member

Leng Han, Ph.D.

Committee Member

Jian Hu, Ph.D.

Committee Member

Dung-Fang Lee, Ph.D.

Committee Member

Hussein A. Abbas, M.D., Ph.D.

Committee Member

Zhibin Zhang, Ph.D.

Abstract

The tumor microenvironment is increasingly recognized as a dynamic regulator of cancer progression, metastatic dissemination, and therapeutic response. In prostate cancer, stromal remodeling and immune exclusion are major barriers to durable disease control, particularly in advanced and metastatic disease, where responses to immune checkpoint blockade remain limited. Cancer-associated fibroblasts and myofibroblast-like stromal states can promote extracellular matrix remodeling, tumor-stroma crosstalk, immune suppression, and metastatic niche formation. However, the systemic mechanisms that regulate stromal cell plasticity and thereby shape anti-tumor immunity remain incompletely understood. Exercise has emerged as a modifiable systemic intervention associated with improved cancer outcomes, including in prostate cancer, but the molecular pathways linking exercise to stromal remodeling and immune activation are poorly defined. This study investigates how systemic modulation by exercise reshapes the prostate tumor microenvironment and identifies ciliary neurotrophic factor (CNTF) as an exercise-associated mediator that suppresses tumor-promoting stromal activation, enhances anti-tumor immunity, and limits prostate cancer progression.

Using the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, this study examined whether mild treadmill exercise alters spontaneous prostate cancer progression. Exercise reduced primary tumor burden, prolonged survival, decreased metastatic dissemination, and shifted tumor histopathology toward less aggressive disease states. Multiplex immunohistochemistry and histologic analysis revealed that exercise was associated with reduced myofibroblast features in the tumor stroma. Single-cell RNA sequencing further demonstrated that exercise remodels multiple cellular compartments within the tumor microenvironment. Exercised tumors showed reduced epithelial and tumor representation, increased immune and stromal compartments, enhanced T-cell infiltration, and a pronounced shift in stromal composition away from proto-myofibroblast and mature myofibroblast states toward fibroblast states. Pseudotime trajectory analysis supported a fibroblast-to-proto-myofibroblast-to-myofibroblast continuum that was altered by exercise, suggesting that systemic exercise cues influence stromal state transitions rather than simply changing stromal abundance.

To identify circulating mediators of exercise-induced tumor remodeling, serum cytokines were profiled in healthy human donors stratified by exercise level. CNTF emerged as an exercise-associated circulating factor elevated in highly active donors, and this increase was further validated in exercised TRAMP mice. Because CNTF signals through the CNTF receptor complex, the clinical relevance of CNTF receptor α (CNTFR) was evaluated in prostate cancer datasets and human tissue microarrays. CNTFR expression was reduced in prostate tumors compared with normal prostate tissue and was associated with favorable clinical features, including improved survival, lower lymph node metastasis, and less aggressive disease parameters. Multiplex imaging of human prostate cancer tissues showed that CNTFR-high regions were associated with reduced α-SMA and PDGFRβ stromal features and increased CD8⁺ T-cell infiltration. These findings suggest that CNTFR expression marks a stromal-immune state characterized by reduced myofibroblast activation and enhanced immune permissiveness.

Mechanistically, this study investigated whether CNTF regulates tumor-stroma crosstalk. Conditional media and indirect co-culture experiments using human prostate cancer cells and fibroblast cells demonstrated that prostate cancer cell–derived soluble factors are sufficient to induce a myofibroblast-like transcriptional program in fibroblasts, including increased expression of stromal remodeling and contractile genes such as ACTA2, MMP9, VCAN, SPARC, and related extracellular matrix-associated programs. Recombinant CNTF attenuated the capacity of prostate cancer cells to induce myofibroblast differentiation, indicating that CNTF interrupts tumor-derived stromal instruction. RNA sequencing of CNTF-treated tumor cells identified suppression of matrix- and stromal-interaction-associated genes, including EDIL3, suggesting that CNTF remodels the tumor secretome to reduce pro-myofibroblast signaling and restrain tumor-driven stromal activation.

Finally, the therapeutic relevance of CNTF-mediated stromal reprogramming was evaluated in vivo. In the orthotopic TRAMP-C2 prostate cancer model, recombinant CNTF suppressed tumor growth and enhanced the efficacy of PD-1 blockade. This therapeutic effect was accompanied by reduced myofibroblast features and increased CD8⁺ T-cell infiltration, supporting the concept that stromal remodeling can improve immune responsiveness in prostate cancer. In the experimental RM1 bone metastasis model, recombinant CNTF reduced metastatic burden, decreased osteolytic lesion development, and altered stromal features within metastatic bone lesions. These data suggest that CNTF has activity in both primary prostate tumors and metastatic microenvironments where tumor-stroma interactions are critical for disease progression.

Together, we reveal that systemic exercise-induced CNTF engages CNTFR signaling to reprogram stromal cell states, restrain tumor-driven myofibroblast activation, promote CD8⁺ T-cell infiltration, enhance immune checkpoint blockade response, and suppress metastatic progression. These findings define stromal cell reprogramming as a mechanism by which systemic modulation can enhance anti-tumor immunity in prostate cancer. More broadly, this work highlights the therapeutic potential of targeting systemic tumor-stroma-immune communication to overcome immune resistance and metastatic progression in prostate cancer.

Keywords

Prostate Cancer, Exercise, Tumor Microenvironment (TME), Cancer-Associated Fibroblasts (CAFs), Ciliary neurotrophic factor (CNTF), Immune checkpoint Inhibitors, PD-1 Blockade

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Available for download on Thursday, August 05, 2027

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