CD39-associated myeloid-T-cell coordination within an immunoregulatory neighborhood linked to treatment resistance in triple-negative breast cancer.
13 affiliations
- 1Department of Biliary Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- 2Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- 3Biliary Tract Disease Institute, Fudan University, Shanghai, 200032, China.
- 4Shanghai Biliary Tract Minimal Invasive Surgery and Materials Engineering Research Center, Shanghai, 200032, China.
- 5Department of Musculoskeletal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- 6Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- 7Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- 8Division of Breast Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China. [email protected].
- 9Department of Biliary Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. [email protected].
- 10Department of General Surgery, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China. [email protected].
- 11Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai, 200032, China. [email protected].
- 12Biliary Tract Disease Institute, Fudan University, Shanghai, 200032, China. [email protected].
- 13Shanghai Biliary Tract Minimal Invasive Surgery and Materials Engineering Research Center, Shanghai, 200032, China. [email protected].
Abstract
Background
Immunotherapy efficacy in triple-negative breast cancer (TNBC) remains limited, partly due to mechanisms of immune suppression within the tumor microenvironment (TME). Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1, encoding cluster of differentiation 39, CD39) is a key immunoregulatory ectonucleotidase, but its treatment-associated distribution and coordination across myeloid and T-cell states in TNBC remain incompletely characterized.Methods
We re-analyzed a single-cell RNA sequencing (scRNA-seq) dataset comprising 156120 immune cells from 27 tumor and metastatic samples across 14 patients with TNBC. Trajectory and cell-cell communication analyses were complemented by NicheNet, independent single-cell and bulk transcriptomic validation, CosMx spatial transcriptomics, and multiplex immunofluorescence. CD39 protein expression and its association with survival were evaluated in an independent cohort of 112 patients with TNBC using immunohistochemistry (IHC), Kaplan-Meier analysis, and multivariable Cox proportional hazards regression. Three signed-R²-based summary indices-treatment contribution (TC), ENTPD1 dynamic index (EDI), and tumor response index (TRI)-were applied to summarize treatment-associated immune dynamics.Results
ENTPD1 expression was observed across macrophage and regulatory T-cell states, including CD4⁺CD39⁺ Tregs. Higher macrophage ENTPD1 expression was associated with M2-related programs, attenuated stimulator of interferon genes (STING)-type I interferon signaling, and reduced antigen-presentation programs. Cell-cell communication analysis revealed preferential interactions between myeloid cells and CD4⁺CD39⁺ T cells. Inferred lymphotoxin (LT) signaling involving CD4⁺CD39⁺ T cells and myeloid populations was higher in non-responders. Cross-cohort and patient-level analyses supported coordinated CD39-associated immune programs, while spatial transcriptomics and representative multiplex immunofluorescence imaging visualized the implicated populations within shared tumor regions. In the independent IHC cohort, high tissue-level CD39 expression remained independently associated with shorter overall survival (OS) after adjustment for age group and American Joint Committee on Cancer (AJCC) stage.Conclusions
ENTPD1/CD39 was associated with coordinated myeloid and T-cell states, an adenosine-related immunoregulatory context, and reduced response to anti-programmed death-ligand 1 (PD-L1) therapy plus chemotherapy in TNBC. These findings support further evaluation of ENTPD1/CD39-associated immune states in the context of immune checkpoint blockade (ICB). High tissue-level CD39 expression was independently associated with shorter OS in an independent clinical cohort.
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BibTeX
@article{hu2026cd39associated,
title = {{CD39-associated myeloid-T-cell coordination within an immunoregulatory neighborhood linked to treatment resistance in triple-negative breast cancer.}},
author = {Zihan Hu and Haoyu Zheng and Cheng Jin and Guoguo Shang and Linzi Song and Shijie Xu and Jiaying Liu and Fuqing Xiang and Yuxuan Zheng and Jingjing Ma and Xiaojian Ni},
journal = {Breast cancer research : BCR},
year = {2026},
month = aug,
doi = {10.1186/s13058-026-02375-9},
url = {https://europepmc.org/article/MED/43010016},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - CD39-associated myeloid-T-cell coordination within an immunoregulatory neighborhood linked to treatment resistance in triple-negative breast cancer.
AU - Zihan Hu
AU - Haoyu Zheng
AU - Cheng Jin
AU - Guoguo Shang
AU - Linzi Song
AU - Shijie Xu
AU - Jiaying Liu
AU - Fuqing Xiang
AU - Yuxuan Zheng
AU - Jingjing Ma
AU - Xiaojian Ni
PY - 2026
DA - 2026/08/14
JO - Breast cancer research : BCR
DO - 10.1186/s13058-026-02375-9
UR - https://europepmc.org/article/MED/43010016
AB - Background Immunotherapy efficacy in triple-negative breast cancer (TNBC) remains limited, partly due to mechanisms of immune suppression within the tumor microenvironment (TME). Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1, encoding cluster of differentiation 39, CD39) is a key immunoregulatory ectonucleotidase, but its treatment-associated distribution and coordination across myeloid and T-cell states in TNBC remain incompletely characterized.Methods We re-analyzed a single-cell RNA sequencing (scRNA-seq) dataset comprising 156120 immune cells from 27 tumor and metastatic samples across 14 patients with TNBC. Trajectory and cell-cell communication analyses were complemented by NicheNet, independent single-cell and bulk transcriptomic validation, CosMx spatial transcriptomics, and multiplex immunofluorescence. CD39 protein expression and its association with survival were evaluated in an independent cohort of 112 patients with TNBC using immunohistochemistry (IHC), Kaplan-Meier analysis, and multivariable Cox proportional hazards regression. Three signed-R²-based summary indices-treatment contribution (TC), ENTPD1 dynamic index (EDI), and tumor response index (TRI)-were applied to summarize treatment-associated immune dynamics.Results ENTPD1 expression was observed across macrophage and regulatory T-cell states, including CD4⁺CD39⁺ Tregs. Higher macrophage ENTPD1 expression was associated with M2-related programs, attenuated stimulator of interferon genes (STING)-type I interferon signaling, and reduced antigen-presentation programs. Cell-cell communication analysis revealed preferential interactions between myeloid cells and CD4⁺CD39⁺ T cells. Inferred lymphotoxin (LT) signaling involving CD4⁺CD39⁺ T cells and myeloid populations was higher in non-responders. Cross-cohort and patient-level analyses supported coordinated CD39-associated immune programs, while spatial transcriptomics and representative multiplex immunofluorescence imaging visualized the implicated populations within shared tumor regions. In the independent IHC cohort, high tissue-level CD39 expression remained independently associated with shorter overall survival (OS) after adjustment for age group and American Joint Committee on Cancer (AJCC) stage.Conclusions ENTPD1/CD39 was associated with coordinated myeloid and T-cell states, an adenosine-related immunoregulatory context, and reduced response to anti-programmed death-ligand 1 (PD-L1) therapy plus chemotherapy in TNBC. These findings support further evaluation of ENTPD1/CD39-associated immune states in the context of immune checkpoint blockade (ICB). High tissue-level CD39 expression was independently associated with shorter OS in an independent clinical cohort.
SN - 1465-5411
SN - 1465-542X
ER -