BACKGROUND: For patients with locally advanced esophagogastric cancer, the standard of care in the UK is neoadjuvant chemotherapy (NAC) followed by surgery. Prehabilitation exercise training can improve physiological function and fitness. If such improvements translate to increased immune infiltration of tumors, exercise could be prescribed as an immune adjuvant during NAC and potentially improve clinical outcomes. As such, we aimed to determine whether prehabilitation increased tumor infiltrating lymphocytes (TILs). METHODS: We assessed 22 patients with locally advanced esophageal cancer on a randomized control trial comparing 16 weeks of low-to-moderate intensity twice weekly supervised and thrice weekly home-based exercise (Prehab: n = 11) to no prehabilitation (Control: n = 11). Our primary outcome was to compare tumor-immune responses between Controls and Prehab. We compared formalin-fixed paraffin-embedded tumors by high-resolution multispectral immunohistochemistry (mIHC) and oString spatial transcriptomics. Secondarily, we determined relationships between changes in fitness to the exercise training and tumor-immune measures. Specifically, we assessed percentage changes in peak cardiorespiratory fitness as assessed by peak oxygen uptake (VO2peak) before NAC (Baseline) and after 8 weeks of NAC (Post-NAC), and changes between Baseline and following 8 weeks of NAC recovery before surgery (Pre-surgery) and correlated changes in fitness with tumor-immune responses. Finally, as an exploratory aim, we assessed clinical outcomes between groups, including survival, therapy tolerance, and tumor regrading. RESULTS: We observed that Prehab had significantly more CD8+ lymphocytes in their tumors (mean difference (diff) 1.79, 95% confidence interval (95% CI) 0.76 to 2.82, p < 0.001) and their stroma (mean diff 1.59, 95% CI 0.66 to 2.52, p < 0.001) than the Controls. When normalized to total numbers of TILs, Prehab had higher levels of CD56+ NK cells (median diff 0.87, 95% CI 0.25 to 2.18), p = 0.0274), consisting primarily of CD56dim NK cells (median diff 0.48, 95% CI 0.03 to 2.53), p = 0.0464). Evaluation of the presence and localization of tumor-associated tertiary lymphoid structures (TLS) in the esophageal tumors revealed that most TLS were in the peritumoral regions. Prehab had a higher TLS cell density (cells/mm2; median diff 18,959, 95% CI 13,518 to 22,635), p < 0.001) and more clearly defined germinal centers indicative of mature TLS visually. We observed that Prehab maintained their VO2peak during NAC while the Controls' VO2peak reduced by 9.0% +/- 10.2% (mean +/- SD) (Post-NAC: p = 0.018). Pre-surgery, Prehab VO2peak was a clinically meaningful 3.27 +/- 1.31 mL/kg/min higher than Controls (p = 0.022). Between Baseline and Post-NAC, where the Prehab maintained VO2peak better than Controls, there were significant positive associations with percentage changes in VO2peak and the frequencies of CD8+ TILs (r 0.531, p = 0.016), programmed death-ligand 1+ (PDL1+) cells (r 0.566, p = 0.009), and granzyme B+ (GrzB+) TILs (r 0.592, p = 0.007). Similar relationships were observed for changes in VO2peak from Baseline to Pre-Surgery only in the Prehab group. We observed no differences between groups regarding clinical outcomes such as survival, therapy tolerance, or tumor regrading. CONCLUSION: We show that exercise training during NAC, which promotes higher levels of cardiorespiratory fitness than no exercise, is associated with increased frequencies of TILs and maturity of TLS. These data suggest that exercise during NAC enhances the immune system. Future studies are warranted to understand the clinical consequences of this.

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