This study is the first to demonstrate that prehabilitation exercise training during neoadjuvant chemotherapy (NAC) for esophageal adenocarcinoma significantly enhances the maturity of tumor-infiltrating lymphocytes and tertiary lymphoid structures, providing potential mechanistic support for immune modulation.
Literature Overview
This article, 'Prehabilitation during neoadjuvant chemotherapy results in an enhanced immune response in esophageal adenocarcinoma tumors: A randomized controlled trial', published in the Journal of Sport and Health Science, reviews and summarizes findings from a randomized controlled trial investigating the impact of prehabilitation exercise training during neoadjuvant chemotherapy on the immune microenvironment of esophageal adenocarcinoma patients.
Background Knowledge
In esophageal adenocarcinoma treatment, surgery following neoadjuvant chemotherapy (NAC) is the standard pathway. However, NAC may lead to physiological deterioration, including reduced cardiopulmonary fitness and muscle mass. Exercise interventions have been extensively studied as non-pharmacological strategies to maintain or improve patient fitness. Emerging evidence suggests that physical activity can promote immune cell infiltration (e.g., CD8+ T cells and CD56+ NK cells) through muscle-derived cytokines (myokines) like IL-6 and IL-15, enhancing immune surveillance. Tertiary lymphoid structures (TLS), organized local immune structures within the tumor microenvironment, demonstrate improved prognosis when mature. However, the relationship between exercise and TLS maturation in human esophageal adenocarcinoma remains understudied. This research pioneers low-to-moderate intensity exercise intervention during NAC, assessing its immunomodulatory effects and offering novel clinical insights into cancer immunotherapy.
Research Methods and Experiments
The study enrolled 22 esophageal adenocarcinoma patients undergoing neoadjuvant chemotherapy, randomized into a prehabilitation group (n=11) and control group (n=11). The prehabilitation group received 16 weeks of low-to-moderate intensity aerobic and resistance training, including two supervised weekly sessions and three home-based sessions. Primary endpoints evaluated changes in tumor-infiltrating lymphocyte (TIL) frequency using multiplex immunohistochemistry (mIHC) and NanoString spatial transcriptomics. Secondary endpoints assessed correlations between fitness changes and immune parameters.
Key Conclusions and Perspectives
Research Significance and Prospects
This study provides the first evidence in human esophageal adenocarcinoma that exercise training enhances TIL frequency and TLS maturity, offering direct support for exercise as an immunomodulatory agent. Future research should evaluate whether high-intensity interval training (HIIT) yields greater fitness improvements and immune activation, incorporating myokine profiling and TLS functional analysis to elucidate mechanisms. Investigations into exercise's applicability across other tumor types and synergies with chemotherapy regimens (e.g., FLOT) are also warranted.
Conclusion
This research demonstrates that low-to-moderate intensity prehabilitation exercise during neoadjuvant chemotherapy significantly increases CD8+ TIL frequency and TLS maturation in esophageal adenocarcinoma patients, with fitness changes positively correlated to immune enhancement. While clinical outcomes like survival remain unchanged, the immunomodulatory effects highlight exercise as a promising adjuvant strategy in cancer therapy. Larger multi-center trials with extended follow-up are required to validate long-term benefits on survival and recurrence. Future studies should explore whether combining exercise with advanced chemotherapy or higher-intensity regimens can further amplify anti-tumor immunity. This work provides foundational evidence supporting exercise integration in tumor immunotherapy protocols.
