Neoadjuvant chemotherapy induces transient, regimen-specific immune stromal reprogramming in pancreatic ductal adenocarcinoma
- 1School of Science, Faculty of Science Medicine and Health, University of Wollongong, Wollongong, NSW, Australia.
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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BibTeX
@misc{minaei2026neoadjuvant,
title = {{Neoadjuvant chemotherapy induces transient, regimen-specific immune stromal reprogramming in pancreatic ductal adenocarcinoma}},
author = {E. Minaei and D. Cox and A. S. Thind and G. Tincknell and L. A. Coleman and S. J. Wade and N. Islam and D. Waring and M. Ahuja and J. La Malfa and K. S. Haghighi and M. Ranson and M. Aghmesheh and R. Sluyter and E. M. OReilly and K. L. Vine-Perrow},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.07.749769},
url = {https://www.biorxiv.org/content/10.64898/2026.09.07.749769v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Neoadjuvant chemotherapy induces transient, regimen-specific immune stromal reprogramming in pancreatic ductal adenocarcinoma
AU - E. Minaei
AU - D. Cox
AU - A. S. Thind
AU - G. Tincknell
AU - L. A. Coleman
AU - S. J. Wade
AU - N. Islam
AU - D. Waring
AU - M. Ahuja
AU - J. La Malfa
AU - K. S. Haghighi
AU - M. Ranson
AU - M. Aghmesheh
AU - R. Sluyter
AU - E. M. OReilly
AU - K. L. Vine-Perrow
PY - 2026
DA - 2026/09/07
PB - bioRxiv
DO - 10.64898/2026.09.07.749769
UR - https://www.biorxiv.org/content/10.64898/2026.09.07.749769v1
AB - 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.
ER -