TY - JOUR
T1 - Enhanced antitumour immunity following neoadjuvant chemoradiotherapy mediates a favourable prognosis in women with resected pancreatic cancer
AU - van Eijck, Casper W. F.
AU - Mustafa, Dana A. M.
AU - Vadgama, Disha
AU - de Miranda, Noel F. C. C.
AU - Groot Koerkamp, Bas
AU - van Tienhoven, Geertjan
AU - Dutch Pancreatic Cancer Group (DPCG)
AU - van der Burg, Sjoerd H.
AU - Malats, N. ria
AU - van Eijck, Casper H. J.
N1 - Funding Information: This work was financially supported by the Survival with Pancreatic Cancer Foundation (www.supportcasper.nl) (grant number OVIT17-06). Publisher Copyright: © 2023 BMJ Publishing Group. All rights reserved.
PY - 2023/9/14
Y1 - 2023/9/14
N2 - Background: This study investigates sex disparities in clinical outcomes and tumour immune profiles in patients with pancreatic ductal adenocarcinoma (PDAC) who underwent upfront resection or resection preceded by gemcitabine-based neoadjuvant chemoradiotherapy (nCRT). Methods: Patients originated from the PREOPANC randomised controlled trial. Upfront surgery was performed in 82 patients, and 66 received nCRT before resection. The impact of sex on overall survival (OS) was investigated using Cox proportional hazards models. The immunological landscape within the tumour microenvironment (TME) was mapped using transcriptomic and spatial proteomic profiling. Results: The 5-year OS rate differed between the sexes following resection preceded by nCRT, with 43% for women compared with 22% for men. In multivariate analysis, the female sex was a favourable independent prognostic factor for OS only in the nCRT group (HR 0.19; 95% CI 0.07 to 0.52). Multivariate heterogeneous treatment effects analysis revealed a significant interaction between sex and treatment, implying increased nCRT efficacy among women with resected PDAC. The TME of women contained fewer protumoural CD163+MRC1+M2 macrophages than that of men after nCRT, as indicated by transcriptomic and validated using spatial proteomic profiling. Conclusion: PDAC tumours of women are more sensitive to gemcitabine-based nCRT, resulting in longer OS after resection compared with men. This may be due to enhanced immunity impeding the infiltration of protumoral M2 macrophages into the TME. Our findings highlight the importance of considering sex disparities and mitigating immunosuppressive macrophage polarisation for personalised PDAC treatment.
AB - Background: This study investigates sex disparities in clinical outcomes and tumour immune profiles in patients with pancreatic ductal adenocarcinoma (PDAC) who underwent upfront resection or resection preceded by gemcitabine-based neoadjuvant chemoradiotherapy (nCRT). Methods: Patients originated from the PREOPANC randomised controlled trial. Upfront surgery was performed in 82 patients, and 66 received nCRT before resection. The impact of sex on overall survival (OS) was investigated using Cox proportional hazards models. The immunological landscape within the tumour microenvironment (TME) was mapped using transcriptomic and spatial proteomic profiling. Results: The 5-year OS rate differed between the sexes following resection preceded by nCRT, with 43% for women compared with 22% for men. In multivariate analysis, the female sex was a favourable independent prognostic factor for OS only in the nCRT group (HR 0.19; 95% CI 0.07 to 0.52). Multivariate heterogeneous treatment effects analysis revealed a significant interaction between sex and treatment, implying increased nCRT efficacy among women with resected PDAC. The TME of women contained fewer protumoural CD163+MRC1+M2 macrophages than that of men after nCRT, as indicated by transcriptomic and validated using spatial proteomic profiling. Conclusion: PDAC tumours of women are more sensitive to gemcitabine-based nCRT, resulting in longer OS after resection compared with men. This may be due to enhanced immunity impeding the infiltration of protumoral M2 macrophages into the TME. Our findings highlight the importance of considering sex disparities and mitigating immunosuppressive macrophage polarisation for personalised PDAC treatment.
KW - CHEMOTHERAPY
KW - MACROPHAGES
KW - PANCREATIC CANCER
KW - PANCREATIC SURGERY
KW - RADIOTHERAPY
UR - http://www.scopus.com/inward/record.url?scp=85172327715&partnerID=8YFLogxK
U2 - https://doi.org/10.1136/gutjnl-2023-330480
DO - https://doi.org/10.1136/gutjnl-2023-330480
M3 - Article
C2 - 37709493
SN - 0017-5749
VL - 73
SP - 311
EP - 324
JO - Gut
JF - Gut
IS - 2
M1 - 330480
ER -