Prehabilitation During Neoadjuvant Chemotherapy Results In An Enhanced Tumour Immune Response In Oesophageal Cancer.

PURPOSE. For patients with locally advanced oesophagogastric cancer, the standard of care is neoadjuvant chemotherapy (NAC) followed by surgery. Prehabilitation exercise can improve physiological function and may reduce tumour burden. As no studies have assessed tumour infiltrating lymphocyte (TIL) responses in humans during NAC undergoing prehabilitation, we aimed to determine whether prehabilitation increased TILs. METHODS. We enrolled 22 patients with locally advanced oesophageal cancer on a randomised control trial comparing 16 weeks low-to-moderate intensity twice weekly supervised and thrice weekly home-based exercise (Prehab: N = 11) to Usual Care (UC: N = 11). We analysed peak cardiorespiratory fitness (VO2peak) before (Base), after 8 weeks of NAC (post-NAC) and following 8 weeks of NAC recovery before surgery (Pre-Surgery). We assessed tumours by high-resolution multispectral immunohistochemistry (mIHC) by PhenoImager HT and spatial transcriptomics by NanoString nCounter PanCancer IO 360 Panel. RESULTS. We observed VO2peak maintenance during NAC for Prehab that increased by 9.4% ± 7.6% at pre-surgery (p = 0.010) and a 9.0% ± 10.2% reduction in VO2peak Post-NAC in UC (p = 0.018). Prehab VO2peak was higher than UC at pre-surgery by a clinically meaningful 3.3 ± 1.3 mL/kg/min (p = 0.022). mIHC revealed a higher frequency of CD8+ lymphocytes in the tumours (3.2% ± 3.3% v 1.4% ± 1.3%, p < 0.001) and stroma (3.2% ± 2.4% v 1.6% ± 1.4%, p < 0.001) for Prehab compared to UC. NanoString revealed that the levels of CD56+ NK (p = 0.0274) and CD56dim NK TILs (p = 0.0464) but not CD8+ T cells (p = 0.276) were higher in Prehab tumours. Further, mIHC revealed that Prehab had increased maturity of tertiary lymphoid structures (TLS) (p < 0.001) that contained higher levels of CD4+, CD8+, CD68+ and DC-LAMP+ immune cells (all p < 0.05). We observed positive relationships between the changes in VO2peak from Base to Post-NAC and the frequencies of CD8+ TILS (r = .531, p = 0.016), PDL1+ cells (r = .566, p = 0.009), and GrzB+ TILS (r = .592, p = 0.007). CONCLUSION. We show that exercise training during NAC, which improves cardiorespiratory fitness, is associated with increased frequencies of TILs and maturity of TLS. These data suggest that exercise during NAC enhances the immune system possibly to be suitable for immunotherapy. Macmillan Cancer Support and NIHR