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Tryptophan and Brain Disorders / Immune Cells in Cancer · Journal article
Breast Cancer Research · August 14, 2026
Encouraging direction, but not yet definitive.
This study characterizes CD39/ENTPD1 expression across myeloid and T-cell populations in TNBC using single-cell and spatial transcriptomics, identifying coordinated immunoregulatory states associated with reduced response to PD-L1 blockade plus chemotherapy and shorter overall survival. High tissue CD39 expression independently predicts worse OS in an independent IHC cohort, supporting further investigation of CD39-targeted approaches in ICB-treated TNBC.
Retrospective single-cell RNA sequencing analysis with multi-modal validation (spatial transcriptomics, multiplex immunofluorescence) and independent retrospective immunohistochemistry cohort. Patients with triple-negative breast cancer: 14 patients contributing 27 tumor and metastatic samples for scRNA-seq; independent cohort of 112 TNBC patients for IHC-based survival analysis. Intervention: Analysis of CD39/ENTPD1 expression and associated immune states; exposure to anti-PD-L1 therapy plus chemotherapy (treatment response stratification). Compared with: Responders versus non-responders to anti-PD-L1 plus chemotherapy; high versus low tissue CD39 expression.
CD39 expression observed across macrophage and regulatory T-cell states, including CD4+ CD39+ Tregs Higher macrophage ENTPD1 expression associated with M2-related programs and attenuated STING-type I interferon signaling Inferred lymphotoxin signaling involving CD4+ CD39+ T cells and myeloid populations higher in non-responders to anti-PD-L1 plus chemotherapy
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These findings suggest that high CD39 expression in tumor tissue may identify TNBC patients at higher risk of immunotherapy resistance and worse prognosis, potentially warranting evaluation of CD39 inhibition as an adjunct to checkpoint blockade. The mechanistic association between CD39-expressing myeloid and T-cell populations and non-response supports exploring CD39-targeted strategies, though prospective clinical trials are needed.
Comprehensive multi-omics analysis identifying CD39-associated immunoregulatory mechanisms linked to immunotherapy resistance in TNBC, with independent validation and prognostic association, but lacking prospective clinical trial data or intervention outcomes.
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These findings suggest that high CD39 expression in tumor tissue may identify TNBC patients at higher risk of immunotherapy resistance and worse prognosis, potentially warranting evaluation of CD39 inhibition as an adjunct to checkpoint blockade. The mechanistic association between CD39-expressing myeloid and T-cell populations and non-response supports exploring CD39-targeted strategies, though prospective clinical trials are needed.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
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. 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-R 2 -based summary indices-treatment contribution (TC), ENTPD1 dynamic index (EDI), and tumor response index (TRI)-were applied to summarize treatment-associated immune dynamics. 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. 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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