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A single-cell map of intratumoral changes during anti-PD1 treatment of patients with breast cancer
Open accessAbstract
Immune-checkpoint blockade (ICB) combined with neoadjuvant chemotherapy improves pathological complete response in breast cancer. To understand why only a subset of tumors respond to ICB, patients with hormone receptor-positive or triple-negative breast cancer were treated with anti-PD1 before surgery. Paired pre- versus on-treatment biopsies from treatment-naive patients receiving anti-PD1 (n = 29) or patients receiving neoadjuvant chemotherapy before anti-PD1 (n = 11) were subjected to single-cell transcriptome, T cell receptor and proteome profiling. One-third of tumors contained PD1-expressing T cells, which clonally expanded upon anti-PD1 treatment, irrespective of tumor subtype. Expansion mainly involved CD8+ T cells with pronounced expression of cytotoxic-activity (PRF1, GZMB), immune-cell homing (CXCL13) and exhaustion markers (HAVCR2, LAG3), and CD4+ T cells characterized by expression of T-helper-1 (IFNG) and follicular-helper (BCL6, CXCR5) markers. In pre-treatment biopsies, the relative frequency of immunoregulatory dendritic cells (PD-L1+), specific macrophage phenotypes (CCR2+ or MMP9+) and cancer cells exhibiting major histocompatibility complex class I/II expression correlated positively with T cell expansion. Conversely, undifferentiated pre-effector/memory T cells (TCF7+, GZMK+) or inhibitory macrophages (CX3CR1+, C3+) were inversely correlated with T cell expansion. Collectively, our data identify various immunophenotypes and associated gene sets that are positively or negatively correlated with T cell expansion following anti-PD1 treatment. We shed light on the heterogeneity in treatment response to anti-PD1 in breast cancer.
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“These cell subsets show different responses to anti-PD(L)-1 therapies,”
From Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer (2025) · cites this paper as [17]
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“Applying ICB and combination therapies as neoadjuvant treatments provides an opportunity to observe immune cell dynamics in tumor microenvironment (TME) with temporal samples.”
From Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer (2025) · cites this paper as [17]
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Metadata
- Authors
- Bassez, A., Vos, H., Van Dyck, L., Floris, G., Arijs, I., Desmedt, C., Boeckx, B., Vanden Bempt, M., Nevelsteen, I., Lambein, K., Punie, K., Neven, P., Garg, A. D., Wildiers, H., Qian, J., Smeets, A., & Lambrechts, D.
- Affiliations
- VIB-KU Leuven Center for Cancer Biology (BE)
- KU Leuven (BE)
- Universitair Ziekenhuis Leuven (BE)
- Women's Hospital, School of Medicine, Zhejiang University (CN)
- Corresponding author
- Qian, Junbin
- Smeets, Ann
- Lambrechts, Diether
- ORCID
- Venue
- Nature Medicine
- Published
- 2021-05
- Volume
- 27
- Issue
- 5
- Pages
- 820-832
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W3157384750
- Cited by
- 867
- References
- 74
- Citations by year
- 2026: 156 · 2025: 168 · 2024: 234 · 2023: 159 · 2022: 116 · 2021: 33
- FWCI
- 52.64
- Type
- journal article
- Language
- en
- Open access
- green
- lirias.kuleuven.be
- Licence
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- Funders
- Vlaams Supercomputer Centrum
- European Commission (847912)
- Fonds Wetenschappelijk Onderzoek (KOTK/2018/11509/1, C14/18/092, POR/16/040, G0B4620N, C14/19/098, 30837538, G0B6120N)
- KU Leuven (C14/19/098, C14/18/092, POR/16/040, C14/19, 30837538, KOTK/2018/11509/1)
- Kom op tegen Kanker (C14/19/098, 30837538, POR/16/040, KOTK/2018/11509/1)
- Vlaamse regering (VR 2016 2312 Doc.1521/4, 30837538, C14/19/098)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- breast cancer, anti-PD-1 therapy, immune checkpoint blockade, neoadjuvant chemotherapy, tumor immune microenvironment, T cell clonal expansion, CD8+ T cells, CD4+ T cells, T cell exhaustion, tumor-infiltrating macrophages, treatment response heterogeneity, triple-negative breast cancer, hormone receptor-positive breast cancer, single-cell transcriptomics, proteomics
- MeSH terms
- Immune Checkpoint Inhibitors, Dendritic Cells, Female, Humans, Macrophages, Receptors, Antigen, T-Cell, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Neoadjuvant Therapy, Single-Cell Analysis, Programmed Cell Death 1 Receptor, Antibodies, Monoclonal, Humanized, Triple Negative Breast Neoplasms
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