Rayner CJ, Bartlett DB, et al.
Journal of Sport and Health Science, 2025 (in press)
Objective
This randomized controlled trial (RCT) aimed to determine whether exercise-based prehabilitation during neoadjuvant chemotherapy (NAC) can enhance immune responses in tumors of patients with locally advanced esophageal adenocarcinoma, specifically by increasing tumor-infiltrating lymphocytes (TILs) and altering the tumor immune microenvironment.
Methods
- Participants: 22 patients with histologically confirmed esophageal adenocarcinoma were randomly assigned to:
- Prehabilitation (Prehab) group (n = 11): received 16 weeks of low-to-moderate intensity exercise (supervised and home-based),
- Control group (n = 11): received standard care without structured exercise.
- Exercise Intervention: Twice-weekly supervised sessions and thrice-weekly home-based aerobic and resistance training during and after NAC.
- Primary Outcome: Immune profiling of surgically resected tumor tissue using high-resolution multispectral immunohistochemistry (mIHC) and NanoString spatial transcriptomics.
- Secondary Outcomes: Correlation between changes in cardiorespiratory fitness (V̇O2peak) and immune measures; exploratory assessment of clinical outcomes (survival, tumor response, therapy tolerance).
Key Findings
1. Immune Cell Infiltration
- Prehab patients had significantly greater infiltration of CD8⁺ T cells in both tumor tissue (mean difference = 1.79; p < 0.001) and surrounding stroma (mean difference = 1.59; p < 0.001).
- Increased levels of CD56⁺ natural killer (NK) cells were observed, particularly the CD56^dim subset, indicating enhanced innate immune activation.
2. Tertiary Lymphoid Structures (TLS)
- TLS were predominantly peritumoral.
- Prehab was associated with significantly higher TLS cell density (p < 0.001) and visually more mature TLS with defined germinal centers.
3. Cardiorespiratory Fitness and Immune Correlates
- Prehab preserved V̇O2peak during NAC, while Controls experienced a 9% decline.
- Improvements in fitness (V̇O2peak) were significantly correlated with higher frequencies of:
- CD8⁺ TILs (r = 0.531, p = 0.016),
- PDL1⁺ cells (r = 0.566, p = 0.009),
- Granzyme B⁺ TILs (r = 0.592, p = 0.007).
4. Gene Expression (NanoString Analysis)
- Prehab tumors showed elevated expression of immune-related genes (e.g., TNFSF13, MMP1, MET) and reduced expression of genes involved in matrix remodeling, metastasis, and metabolic stress (e.g., PLOD2, VCAM1, EGFR).
- Pathway analysis indicated trends for increased antigen presentation and cytotoxicity signaling in the Prehab group.
5. Clinical Outcomes
- No significant differences between Prehab and Control groups in terms of survival, tumor staging, regression grades, or chemotherapy tolerance.
- One- and three-year survival estimates were similar between groups.
Conclusion
This study demonstrates that prehabilitation exercise during NAC in patients with esophageal adenocarcinoma is associated with:
- Increased infiltration of cytotoxic and innate immune cells into tumors,
- Development of more mature TLS,
- Enhanced immune-related gene expression,
- Maintenance or improvement of aerobic fitness.
Although no short-term clinical outcome differences were observed, the immunological enhancements suggest that exercise during NAC could serve as a non-pharmacologic immune adjuvant, warranting further investigation into its potential to improve long-term cancer outcomes. This may be the future of neoadjuvant chemotherapy regimens. Future clinical trials will hopefully answer that question.
J Sport Health Sci 2025;xxx:101063.
