Neoadjuvant chemotherapy induces transient, regimen-specific immune stromal reprogramming in pancreatic ductal adenocarcinoma

Minaei, E.; Cox, D.; Thind, A. S.; Tincknell, G.; Coleman, L. A.; Wade, S. J.; Islam, N.; Waring, D.; Ahuja, M.; La Malfa, J.; Haghighi, K. S.; Ranson, M.; Aghmesheh, M.; Sluyter, R.; OReilly, E. M.; Vine-Perrow, K. L.

doi:10.64898/2026.09.07.749769

bioRxiv · 10.64898/2026.09.07.749769

Neoadjuvant chemotherapy induces transient, regimen-specific immune stromal reprogramming in pancreatic ductal adenocarcinoma

Minaei, E.·Cox, D.·Thind, A. S.·Tincknell, G.·Coleman, L. A.·Wade, S. J.·Islam, N.·Waring, D.·Ahuja, M.·La Malfa, J.·Haghighi, K. S.·Ranson, M.·Aghmesheh, M.·Sluyter, R.·OReilly, E. M.·Vine-Perrow, K. L.

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Abstract

Background: Neoadjuvant chemotherapy (NAC) is increasingly incorporated into the management of pancreatic ductal adenocarcinoma (PDAC), yet how treatment regimen and timing reshape the tumour-immune microenvironment remains poorly defined. Methods: Targeted immune transcriptomic profiling was performed using NanoString on spatially annotated tumour, stromal, and immune-enriched regions from resected PDAC specimens from 23 patients, including NAC-treated and treatment-naive cohorts. Key findings were validated and spatially localised using Xenium in situ transcriptomics. Results: NAC induced extensive transcriptional remodelling of the tumour microenvironment in a regimen- and time-dependent manner. Tumours resected shortly after FOLFIRINOX exhibited coordinated upregulation and strong spatial coupling of the CXCL12-CXCR4 axis. These correlations were attenuated or reversed at longer post-treatment intervals and following gemcitabine-based therapy. Disrupted stromal coordination of the CCL2-CCR2 axis further highlighted context-dependent effects of chemotherapy on chemokine signalling. Across regions, NT5E (CD73) expression inversely correlated with CD8A, consistent with spatially restricted T cell exclusion. Conclusions: NAC dynamically reprograms the immunestromal landscape of PDAC in a regimen- and timing-dependent manner, revealing a transient post-chemotherapy window of immune remodelling. The clinical significance of this phenomenon requires further investigation to determine whether temporally optimised integration of immunomodulatory and stroma-targeted therapies with NAC can improve patient outcomes.

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Minaei, E., Cox, D., Thind, A. S., Tincknell, G., Coleman, L. A., Wade, S. J., Islam, N., Waring, D., Ahuja, M., La Malfa, J., Haghighi, K. S., Ranson, M., Aghmesheh, M., Sluyter, R., OReilly, E. M., Vine-Perrow, K. L.. 2026-09-11. Neoadjuvant chemotherapy induces transient, regimen-specific immune stromal reprogramming in pancreatic ductal adenocarcinoma. https://doi.org/10.64898/2026.09.07.749769

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