Cited by 867Cancer Immunotherapy and BiomarkersBreast Cancer Treatment StudiesT-cell and B-cell Immunology

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A single-cell map of intratumoral changes during anti-PD1 treatment of patients with breast cancer

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Bassez, Ayse, Vos, Hanne, Van Dyck, Laurien, Floris, Giuseppe, Arijs, Ingrid, Desmedt, Christine, Boeckx, Bram, Vanden Bempt, Marlies, Nevelsteen, Ines, Lambein, Kathleen, Punie, Kevin, Neven, Patrick, Garg, Abhishek D., Wildiers, Hans, Qian, Junbin, Smeets, Ann, Lambrechts, Diether·2021·Nature Medicine

DOI 10.1038/s41591-021-01323-8

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Abstract

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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Immunotherapy for triple-negative breast cancer: A molecular insight into the microenvironment, treatment, and resistance
Bai, X., Ni, J., Beretov, J., Graham, P., & Li, Y. (2021) · Journal of the National Cancer Center · doi:10.1016/j.jncc.2021.06.001 · Cited by 50
“Through single-cell transcriptomics, Bassez, et al. 30 found that intratumoral PD-L1 + CD8 + T cells with the expression of PRF1, GZMB, CCL13, HAVCR2, and LAG3 and PD-L1 + CD4 + T cells with the expression of IFN 𝛾 , BCL6, and CXCR5 clonally expanded in residue BC after pembrolizumab treatment.”
Method
Insulin-like growth factor 2 drives fibroblast-mediated tumor immunoevasion and confers resistance to immunotherapy
Song, D., Wu, Y., Li, J., Liu, J., Yi, Z., Wang, X., Sun, J., Li, L., Wu, Q., Chen, Y., et al. (2024) · Journal of Clinical Investigation · doi:10.1172/jci183366 · Cited by 63
“Despite this, only a fraction of patients tend to respond effectively to immune check-point blockade (ICB), especially in prevalent malignancies such as breast cancer and colorectal cancer (3–5).”
Advancements and applications of single-cell multi-omics techniques in cancer research: Unveiling heterogeneity and paving the way for precision therapeutics
Liang, A., Kong, Y., Chen, Z. H., Qiu, Y., Wu, Y., Zhu, X. M., & Li, Z. (2023) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2023.101589 · Cited by 55
“Bassez et al. [115] employed single-cell multi-omics techniques, including single-cell transcriptome, T-cell receptor, and proteome analysis, to elucidate the heterogeneity of breast cancer response to anti-PD1 therapy and explore the mechanism of neoadjuvant chemotherapy in breast cancer.”
Background
Linked CD4+/CD8+ T cell neoantigen vaccination overcomes immune checkpoint blockade resistance and enables tumor regression
Dolina, J. S., Lee, J., Brightman, S. E., McArdle, S., Hall, S. M., Thota, R. R., Lanka, M., Premlal, A., Greenbaum, J. A., Cohen, E. E. W., et al. (2023) · bioRxiv · doi:10.1101/2023.05.06.539290 · Cited by 47
“18 to mobilize PD-1− Tn and PD-1lo Tprec/prog at the expense of PD-1hi Tex-term cells (Figure 6G and Figure 7E right panels) (70, 71).”
Background
Inferring ligand-receptor cellular networks from bulk and spatial transcriptomic datasets with BulkSignalR
Villemin, J.-P., Bassaganyas, L., Pourquier, D., Boissière‐Michot, F., Cabello‐Aguilar, S., Lopez‐Crapez, E., Tanos, R., Cornillot, E., Turtoï, A., & Colinge, J. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad352 · Cited by 47
“To better characterize a potential bias introduced by the bulk approach, we generated synthetic bulk data (27) from a cohort of 29 primary, untreated breast tumors analyzed in single-cell transcriptomics (28) (Figure S7A).”
Method
Anais Brasileiros de Dermatologia
Gontijo, B., Marques, S., & do Vale, E. C. S. (2004) · Anais Brasileiros de Dermatologia · doi:10.1590/s0365-05962004000500001 · Cited by 47
Temporally restricted activation of IFNβ signaling underlies response to immune checkpoint therapy in mice
Zemek, R. M., Chin, W. L., Fear, V. S., Wylie, B., Casey, T. H., Forbes, C., Tilsed, C. M., Boon, L., Guo, B. B., Bosco, A., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-32567-8 · Cited by 51
Mapping Breast Cancer Microenvironment Through Single-Cell Omics
Tan, Z., Chen, K., Sun, M., Yang, F., Wong, M., Wang, S., & Zheng, H. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.868813 · Cited by 55
“gene set related to T-cell expansion has been identified for the prediction of ICB response (65).”
Background
Single-Cell Transcriptomic Analysis Reveals a Tumor-Reactive T Cell Signature Associated With Clinical Outcome and Immunotherapy Response In Melanoma
Yan, M., Hu, J., Ping, Y., Xu, L., Liao, G., Jiang, Z., Pang, B., Sun, S., Zhang, Y., Xiao, Y., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.758288 · Cited by 49
Mobilizing antigen-presenting mast cells in anti-PD-1-refractory triple-negative breast cancer: a phase 2 trial
Wu, S., Jin, X., Liu, Y., Wang, Z.-Y., Zuo, W., Ma, D., Xiao, Y., Fu, T., Xiao, Y.-L., Chen, L., et al. (2025) · Nature Medicine · doi:10.1038/s41591-025-03776-7 · Cited by 51
“Immunoglobulin, ribosomal, mitochondrial and protein complex genes were not included 6 .”
Immunogenomic cancer evolution: A framework to understand cancer immunosuppression
Kumagai, S., Momoi, Y., & Nishikawa, H. (2025) · Science Immunology · doi:10.1126/sciimmunol.abo5570 · Cited by 46
Mapping and Validation of scRNA-Seq-Derived Cell-Cell Communication Networks in the Tumor Microenvironment
Bridges, K., & Miller‐Jensen, K. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.885267 · Cited by 48
Dissecting the tumor microenvironment in response to immune checkpoint inhibitors via single-cell and spatial transcriptomics
Liu, W., Puri, A., Fu, D., Chen, L., Wang, C., Kellis, M., & Yang, J. (2023) · Clinical & Experimental Metastasis · doi:10.1007/s10585-023-10246-2 · Cited by 48
“Single-cell sequencing was utilized to assess the molecular landscape of tumor biopsies in hormone receptor-positive and triple-negative breast cancer (TNBC) cancer patients treated with anti-PD-1 antibody prior to certain patients receiving neoadjuvant chemotherapy [44].”
Method
Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumours
Hegde, S., Giotti, B., Soong, B. Y., Halász, L., Bérichel, J. L., Schaefer, M. M., Kloeckner, B., Mattiuz, R., Park, M. D., Magen, A., et al. (2025) · Nature · doi:10.1038/s41586-025-09493-y · Cited by 52
“Raw count matrices were obtained from GEO repositories of published studies 37,78,79 , also listed in Supplementary Table 7.”
A single-cell pan-cancer analysis to show the variability of tumor-infiltrating myeloid cells in immune checkpoint blockade
Li, W., Pan, L., Hong, W., Ginhoux, F., Zhang, X., Xiao, C., & Li, X. (2024) · Nature Communications · doi:10.1038/s41467-024-50478-8 · Cited by 46
“These samples consisted of eight cancer types: basal cell carcinoma (BCC), breast cancer, ccRCC, CRC, hepatocellular carcinoma (HCC), head and neck squamous cell carcinoma (HNSCC), intrahepatic cholangiocarcinoma (iCCA), and non-small cell lung cancer (NSCLC) 42 – 48 .”
PD-1 blockade and CDK4/6 inhibition augment nonoverlapping features of T cell activation in cancer
Ali, L. R., Garrido-Castro, A. C., Lenehan, P. J., Böllenrücher, N., Stump, C. T., Dougan, M. L., Goel, S., Shapiro, G. I., Tolaney, S. M., & Dougan, S. K. (2023) · The Journal of Experimental Medicine · doi:10.1084/jem.20220729 · Cited by 40
“Single-cell analysis from breast cancer patients has shown that intratumoral CD103+ resident memory T cells correspond with improved prognosis, although treatment with PD-1 blockade appears to reinvigorate a different population of CD8 effector memory cells characterized by expression of GZMK and EOMES (Bassez et al.,…”
Background
PD-L1 protects tumor-associated dendritic cells from ferroptosis during immunogenic chemotherapy
Xiao, K., Zhang, S., Qi, P., Du, Y., Yao, X., Ng, I.-I., & Tang, H. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114868 · Cited by 40
Dual Immune Checkpoint Blockade Induces Analogous Alterations in the Dysfunctional CD8+ T-cell and Activated Treg Compartment
van der Leun, A. M., Traets, J. J. H., Vos, J. L., Elbers, J. B. W., Patiwael, S., Qiao, X., Machuca-Ostos, M., Thommen, D. S., Haanen, J. B. A. G., Schumacher, T. N., et al. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-0851 · Cited by 47
“3C), provides evidence that intratumoral immune cells in nonresponding tumors do respond to dual PD-1 and CTLA4 blockade, but that this response is insufficient to achieve clinically effective tumor control.”
Background
HEBP2-governed glutamine competition between tumor and macrophages dictates immunotherapy efficacy in triple-negative breast cancer.
Xiao, Y., Xu, Y., Wang, H., Yang, F., Ding, X.-H., Fu, T., Chen, L., Jin, X., Zhao, Y.-X., Wang, Y., et al. (2025) · Cell Metabolism · doi:10.1016/j.cmet.2025.08.009 · Cited by 38
Heterogeneity of tertiary lymphoid structures predicts the response to neoadjuvant therapy and immune microenvironment characteristics in triple-negative breast cancer
Wang, Q., Yu, Y.-S., Wang, C.-X., Jiang, Z., Li, J.-L., Li, X.-F., Huang, X.-W., Song, Y., Li, Z.-H., Tang, S., et al. (2024) · British Journal of Cancer · doi:10.1038/s41416-024-02917-y · Cited by 38
“In a recent study of 29 BC patients, scRNA-seq was used to analyse changes in immune cells before and after anti-PD-1 therapy [29].”
ITGB6 modulates resistance to anti-CD276 therapy in head and neck cancer by promoting PF4+ macrophage infiltration
Zhang, C., Li, K., Zhu, H., Cheng, M., Chen, S., Ling, R., Wang, C., & Chen, D. (2024) · Nature Communications · doi:10.1038/s41467-024-51096-0 · Cited by 39
“Speci ﬁ cally, GZMB + CD8 + T cells, characterized by their expression of Granzyme B, represent a highly activated cytotoxic state and exhibit an enhanced capacity to recognize and eradicate tumor cells 17,18 .”
Background
Dissecting the single-cell transcriptome network in patients with esophageal squamous cell carcinoma receiving operative paclitaxel plus platinum chemotherapy
Chen, Z., Huang, Y., Hu, Z., Zhao, M., Bian, Y., Chen, Z., Zheng, Y., Bi, G., Pang, Y., Zhan, C., et al. (2021) · Oncogenesis · doi:10.1038/s41389-021-00359-2 · Cited by 52
“In our study, we observed levels of exhausted CD8+ T cells were significantly elevated in NACT-ESCC, which was concordant with the findings of previous studies [43, 44].”
Result
Alternations in inflammatory macrophage niche drive phenotypic and functional plasticity of Kupffer cells
Huang, H.-Y., Chen, Y.-Z., Zhao, C., Zheng, X.-N., Yu, K., Yue, J., Ju, H., Shi, Y., & Tian, L. H. (2024) · Nature Communications · doi:10.1038/s41467-024-53659-7 · Cited by 39
“10c), a ﬁ nding consistent with observations in human breast cancer samples 49 .”
Complex Analysis of Single-Cell RNA Sequencing Data
Khozyainova, A. A., Valyaeva, A. A., Arbatsky, M. S., Isaev, S. V., Iamshchikov, P. S., Volchkov, E., Sabirov, M. S., Zainullina, V. R., Chechekhin, V. I., Vorobev, R. S., et al. (2023) · Biochemistry (Moscow) · doi:10.1134/s0006297923020074 · Cited by 47
“Changes in the gene expression in the process of clonal expansion and possible accompanying exhaustion of T cells during antitumor immunotherapy were also investigated at the level of single cells with the help of differential expression analysis [57].”
Background
Tumoral and stromal hMENA isoforms impact tertiary lymphoid structure localization in lung cancer and predict immune checkpoint blockade response in patients with cancer
Modugno, F. D., Carlo, A. D., Spada, S., Palermo, B., D’Ambrosio, L., D’Andrea, D., Morello, G., Belmonte, B., Sperduti, I., Balzano, V., et al. (2024) · EBioMedicine · doi:10.1016/j.ebiom.2024.105003 · Cited by 39
Self-citation
Targeting the lipid kinase PIKfyve upregulates surface expression of MHC class I to augment cancer immunotherapy
Bao, Y., Qiao, Y., Choi, J. E., Zhang, Y., Mannan, R., Cheng, C., He, T., Zheng, Y., Yu, J., Gondal, M. N., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2314416120 · Cited by 39
“To determine whether PIKFYVE expression specifically in malignant cells predicts clinical outcomes of ICB - treated patients, we exploited published single - cell RNA - sequencing datasets representing cancer patients treated with ICB (45–47).”
Cellular dynamics in tumour microenvironment along with lung cancer progression underscore spatial and evolutionary heterogeneity of neutrophil
Peng, H., Wu, X., Liu, S., He, M., Tang, C., Wen, Y., Xie, C. L., Zhong, R., Li, C., Xiong, S., et al. (2023) · Clinical and Translational Medicine · doi:10.1002/ctm2.1340 · Cited by 38
Peripherally-driven myeloid NFkB and IFN/ISG responses predict malignancy risk, survival, and immunotherapy regime in ovarian cancer
Sprooten, J., Vankerckhoven, A., Vanmeerbeek, I., Borràs, D., Berckmans, Y., Wouters, R., Laureano, R. S., Baert, T., Boon, L., Landolfo, C., et al. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-003609 · Cited by 38
Self-citation
The Role of Somatic Mutations on the Immune Response of the Tumor Microenvironment in Prostate Cancer
Melo, C. M., Vidotto, T., Chaves, L. P., Lautert-Dutra, W., dos Reis, R. B., & Squire, J. A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179550 · Cited by 42
“Several of the studies referenced above showed that the heterogeneity and different cellular activities of the myeloid subtypes and other immune cell phenotypes in the TME were partly based on their physical orientation within the tumor or in the surrounding the periphery of the tumor [40,41,112,113].”
Background
Cancer-associated fibroblast-derived extracellular vesicles loaded with GLUT1 inhibitor synergize anti-PD-L1 to suppress tumor growth via degrading matrix stiffness and remodeling tumor microenvironment
Wu, Y., Chen, W., Deng, J., Zhou, X., Chen, J., Yang, Z., Cao, X., Liu, J., Tan, Q., Zhou, E., et al. (2025) · Journal of Controlled Release · doi:10.1016/j.jconrel.2025.113998 · Cited by 38
Interferon regulatory factor-1–expressing astrocytes are epigenetically controlled and exacerbate TBI-associated pathology in mice
Cui, W., Bai, H., Guo, C., Zhou, J., Feng, D., Zhang, S., Gao, F., Han, L., Tian, Y., Dong, J., et al. (2025) · Science Translational Medicine · doi:10.1126/scitranslmed.adr5300 · Cited by 36
Single-cell transcriptomics reveal distinct immune-infiltrating phenotypes and macrophage–tumor interaction axes among different lineages of pituitary neuroendocrine tumors
Lin, S., Dai, Y., Han, C., Han, T., Zhao, L., Wu, R., Liu, J., Zhang, B., Huang, N., Liu, Y., et al. (2024) · Genome Medicine · doi:10.1186/s13073-024-01325-4 · Cited by 39
Radiotherapy-Triggered In Situ Tumor Vaccination Boosts Checkpoint Blockaded Immune Response via Antigen-Capturing Nanoadjuvants
Xu, P., Ma, J., Zhou, Y. C., Gu, Y., Cheng, X., Wang, Y., Wang, Y., & Gao, M. (2023) · ACS Nano · doi:10.1021/acsnano.3c10225 · Cited by 37
Aldehyde dehydrogenase 2-mediated aldehyde metabolism promotes tumor immune evasion by regulating the NOD/VISTA axis
Chen, Y., Sun, J., Liu, J., Wei, Y., Wang, X., Fang, H., Du, H., Huang, J., Li, Q., Ren, G., et al. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2023-007487 · Cited by 40
Comparative analysis of immune infiltrates in head and neck cancers across anatomical sites
Muijlwijk, T., Nijenhuis, D., Ganzevles, S., Brink, A., Ke, C.-L., Fass, J. N., Rajamanickam, V., Leemans, C., Koguchi, Y., Fox, B. A., et al. (2024) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2023-007573 · Cited by 34
Characterization of the tumour microenvironment phenotypes in malignant tissues and pleural effusion from advanced osteoblastic osteosarcoma patients
Zhang, Z., Ji, W., Huang, J., Zhang, Y., Zhou, Y., Zhang, J., Dong, Y., Yuan, T., Yang, Q., Ding, X., et al. (2022) · Clinical and Translational Medicine · doi:10.1002/ctm2.1072 · Cited by 33
Artesunate Nanoplatform Targets the Serine–MAPK Axis in Cancer‐Associated Fibroblasts to Reverse Photothermal Resistance in Triple‐Negative Breast Cancer
Zheng, D., Yan, J., Liu, X., Zhang, Z., Jin, A., Zhao, Y., Bai, L., Quan, M.-Y., Qi, X., Fu, B., et al. (2025) · Advanced Materials · doi:10.1002/adma.202502617 · Cited by 34
CD200 + cytotoxic T lymphocytes in the tumor microenvironment are crucial for efficacious anti–PD-1/PD-L1 therapy
Wang, X., Zha, H., Wu, W., Yuan, T., Xie, S., Jin, Z., Long, H., Yang, F., Wang, Z., Zhang, A., et al. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.abn5029 · Cited by 34
“To validate our result, we obtained scRNA-seq data from an additional cohort with 42 breast cancer patients as a validation cohort and grouped them by their treatment method (18).”
Method
Alpha radionuclide-chelated radioimmunotherapy promoters enable local radiotherapy/chemodynamic therapy to discourage cancer progression
Zhang, J.-J., Li, F.-Z., Yin, Y.-Z., Liu, N., Zhu, M.-Q., Zhang, H., Liu, W., Yang, M., Qin, S., Fan, X., et al. (2022) · Biomaterials Research · doi:10.1186/s40824-022-00290-6 · Cited by 33
“ICB is widely used in a broad range of cancers, such as non-small cell lung cancer [50], clear cell renal cell carcinoma [51], breast cancer [52], melanoma [53], and head and neck cancer [54].”
Background
Dynamic CD8+ T Cell Cooperation with Macrophages and Monocytes for Successful Cancer Immunotherapy
Vermare, A., Guérin, M. V., Peranzoni, E., & Bercovici, N. (2022) · Cancers · doi:10.3390/cancers14143546 · Cited by 42
“Other reports correlate the presence of Programmed death Ligand 1 (PD-L1+) TAMs with the clinical benefit of immunotherapy, indicating that this phenotype might arise from (and likely contribute to) an IFNγ-rich anti-tumor microenvironment (reviewed in [62,69].”
Background
Cytotoxic NK Cells Impede Response to Checkpoint Immunotherapy in Melanoma with an Immune-Excluded Phenotype
Poźniak, J., Roda, N., Landeloos, E., Antoranz, A., Herck, Y. V., Visscher, A. D., Demaerel, P. G., Vanwynsberghe, L., Declercq, J., Gkemisis, C., et al. (2025) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-1208 · Cited by 33
“Notably, a similar association was observed in a scRNA-seq dataset of patients with breast cancer treated with α PD-1 and for which samples were collected 2 to 3 weeks OT (27).”
Self-citation
Paracrine Orchestration of Tumor Microenvironment Remodeling Induced by GLO1 Potentiates Lymph Node Metastasis in Breast Cancer
Xie, J., Liu, W., Deng, X., Wang, H., Ou, X., An, X., Situ, M., Yang, A., Peng, C., He, R., et al. (2025) · Advanced Science · doi:10.1002/advs.202500722 · Cited by 32
Stem-like progenitor and terminally differentiated TFH-like CD4+ T cell exhaustion in the tumor microenvironment
Zhou, W., Kawashima, S., Ishino, T., Kawase, K., Ueda, Y., Yamashita, K., Watanabe, T., Kawazu, M., Dansako, H., Suzuki, Y., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.113797 · Cited by 38
Tumor endothelial cell autophagy is a key vascular‐immune checkpoint in melanoma
Verhoeven, J., Jacobs, K., Rizzollo, F., Lodi, F., Hua, Y., Poźniak, J., Srinivasan, A. N., Houbaert, D., Shankar, G., More, S., et al. (2023) · EMBO Molecular Medicine · doi:10.15252/emmm.202318028 · Cited by 35
“Our data underscore that autophagy is a persuasive TEC-intrinsic immune-evasion factor, which could be fostered in the tumor by the metabolically stressed TME to enforce immunosuppression (Debnath et al , 2023).”
BackgroundMethodInfluentialSelf-citation
IL-6/STAT3 signaling in tumor cells restricts the expression of frameshift-derived neoantigens by SMG1 induction
Meraviglia-Crivelli, D., Villanueva, H., Zheleva, A., Villalba-Esparza, M., Moreno, B., Menon, A. P., Calvo, A., Cebollero, J., Barainka, M., Mozos, I. R. D. L., et al. (2022) · Molecular Cancer · doi:10.1186/s12943-022-01679-6 · Cited by 36
“cancer patients In line with the hypothesis that NMD might function as checkpoint of tumor antigenicity, we interrogated the scRNAseq dataset from the study [21] to see if higher expansion of T cells could be associated with SMG1 changes upon anti-PD-1 antibody treatment (Pembrolizumab).”
BackgroundMethodInfluential
Bulk and Single-Cell Profiling of Breast Tumors Identifies TREM-1 as a Dominant Immune Suppressive Marker Associated With Poor Outcomes
Pullikuth, A., Routh, E. D., Zimmerman, K. D., Chifman, J., Chou, J. W., Soike, M. H., Jin, G., Su, J., Song, Q., Black, M. A., et al. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.734959 · Cited by 33
AKAP12 positive fibroblast determines immunosuppressive contexture and immunotherapy response in patients with TNBC by promoting macrophage M2 polarization
Liu, Z.-K., Hu, S., Zhao, X., Xu, W.-X., Ju, F., Gu, M., Weng, J., & Du, Y. (2024) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-009877 · Cited by 31
Integrating single-cell RNA-seq and bulk RNA-seq to construct prognostic signatures to explore the role of glutamine metabolism in breast cancer
Pei, S., Zhang, P., Chen, H., Zhao, S., Dai, Y., Yang, L., Kang, Y., Zheng, M., Xia, Y., & Xie, H. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1135297 · Cited by 63
Impacts of neoadjuvant chemoradiotherapy on the immune landscape of esophageal squamous cell carcinoma
Wen, J., Fang, S., Hu, Y., Xi, M., Weng, Z., Pan, C., Luo, K., Ling, Y., Lai, R., Xie, X., et al. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2022.104371 · Cited by 40
Single-cell and spatial transcriptome analyses revealed cell heterogeneity and immune environment alternations in metastatic axillary lymph nodes in breast cancer
Mao, X., Zhou, D., Lin, K., Zhang, B., Gao, J. T., Ling, F., Zhu, L., Yu, S., Chen, P., Zhang, C., et al. (2022) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-022-03278-2 · Cited by 33
“Recently, another single-cell study revealed T cell and macrophage trajectories during anti-PD1 treatment, highlighting immune responsiveness during immune checkpoint blockade [16].”
Identification of Hypoxia‐ALCAMhigh Macrophage‐ Exhausted T Cell Axis in Tumor Microenvironment Remodeling for Immunotherapy Resistance
Xun, Z., Zhou, H., Shen, M., Liu, Y., Sun, C., Du, Y., Jiang, Z., Yang, L., Zhang, Q. H., Lin, C., et al. (2024) · Advanced Science · doi:10.1002/advs.202309885 · Cited by 27
The tumor microenvironment and triple-negative breast cancer aggressiveness: shedding light on mechanisms and targeting
Furukawa, N., Stearns, V., Santa-Maria, C. A., & Popel, A. S. (2022) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2022.2170779 · Cited by 31
“PD-1) treatment [70] and atezolizumab (anti-PD-L1) treat-”
Background
Dissecting the heterogeneity of the microenvironment in primary and recurrent nasopharyngeal carcinomas using single-cell RNA sequencing
Peng, W.-S., Zhou, X., Yan, W.-B., Li, Y.-J., Du, C.-R., Wang, X.-S., Shen, C.-Y., Wang, Q.-F., Ying, H.-M., Lu, X.-G., et al. (2022) · OncoImmunology · doi:10.1080/2162402x.2022.2026583 · Cited by 38
“51 A subset of PD1 + CD8 + T cells expressing T cell activation markers also predicted a good respond to ICIs in NSCLC. 52 These signatures were consistent with those that we defined in rNPC and explained the good response rate to ICIs in recurrent/metastatic NPC. 53–56 Here, we found that…”
HMMR triggers immune evasion of hepatocellular carcinoma by inactivation of phagocyte killing
Wu, H., Liu, Y., Liu, Q., Li, Z., Wan, Y., Cao, C., Wu, B., Liu, M., Liang, R., Hu, L., et al. (2024) · Science Advances · doi:10.1126/sciadv.adl6083 · Cited by 26
“In this study, we found that loss of HMMR could enhance the infiltration of CD8 + T cells, which suggested that HMMR could be used as a molecular target whose modulation could be synergistic with anti–PD-1 ( 40 ).”
Background
C5aR1 inhibition reprograms tumor associated macrophages and reverses PARP inhibitor resistance in breast cancer
Li, X., Poire, A., Jeong, K. J., Zhang, D., Ozmen, T. Y., Chen, G., Sun, C., & Mills, G. B. (2024) · Nature Communications · doi:10.1038/s41467-024-48637-y · Cited by 31
“As indicated in other studies with different TAM subsets couldexpress a mixture of genes associated with pro-and anti-in ﬂ ammatory subtypes 44,46,47 and also found in our study, TAM_C0, TAM_C1 and TAM_C4 were comprised a mixture of pro-and anti-in ﬂ ammatory phenotypes.”
Tryptophan metabolism regulates inflammatory macrophage polarization as a predictive factor for breast cancer immunotherapy
Xue, L., Wang, C., Qian, Y., Zhu, W., Liu, L., Yang, X., Zhang, S., & Luo, D. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.111196 · Cited by 30
Linked CD4+/CD8+ T cell neoantigen vaccination overcomes immune checkpoint blockade resistance and enables tumor regression
Dolina, J. S., Lee, J., Brightman, S. E., McArdle, S., Hall, S. M., Thota, R. R., Zavala, K. S., Lanka, M., Premlal, A. L. R., Greenbaum, J., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci164258 · Cited by 68
“Tex-term subpopulations (metaclusters 17 and 19) were observed to be expanded by Mut_48 vaccination alone; however, this was halted by anti-PD-1 treatment, known to mobilize PD-1− Tn and PD-1 lo Tprec/prog at the expense of PD-1hi Tex-term cells (Figure 8F and Figure 9B) (67, 68).”
Background
A single-cell transcriptomic landscape of innate and adaptive intratumoral immunity in triple negative breast cancer during chemo- and immunotherapies
Carpen, L., Falvo, P., Orecchioni, S., Mitola, G., Hillje, R., Mazzara, S., Mancuso, P., Pileri, S. A., Raveane, A., & Bertolini, F. (2022) · Cell Death Discovery · doi:10.1038/s41420-022-00893-x · Cited by 31
“Immune cellular landscape in the two mouse TNBC TMEs.”
BackgroundInfluential
Tumour-derived microparticles obtained through microwave irradiation induce immunogenic cell death in lung adenocarcinoma
Wu, Y., Chen, W., Deng, J., Cao, X., Yang, Z., Chen, J., Tan, Q., Zhou, E., Li, M., Liu, J., et al. (2025) · Nature Nanotechnology · doi:10.1038/s41565-025-01922-3 · Cited by 30
“Recent studies have indicated that these experienced T cells are specifically derived from tumour-specific cytotoxic T cells 31 , correlated with immune check-point blockade therapy response 32 .”
CD8+ T-cell exhaustion: Impediment to triple-negative breast cancer (TNBC) immunotherapy
Feng, D., Pu, D., Ren, J., Liu, M., Zhang, Z., Liu, Z., & Li, J. (2024) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2024.189193 · Cited by 26
Single cell analyses reveal the PD-1 blockade response-related immune features in hepatocellular carcinoma
Li, Y., Li, F., Xu, L., Shi, X., Xue, H., Liu, J., Bai, S., Wu, Y., Zhao, Y., Xue, F., et al. (2024) · Theranostics · doi:10.7150/thno.95971 · Cited by 32
“In tumors, an immunosuppressive TME can be established by such cells as tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), neutrophils, and regulatory T cells (Tregs) [10, 13, 14].”
Background
Batf3+ DCs and the 4-1BB/4-1BBL axis are required at the effector phase in the tumor microenvironment for PD-1/PD-L1 blockade efficacy
Ziblat, A., Horton, B. L., Higgs, E. F., Hatogai, K., Martinez, A., Shapiro, J. W., Kim, D. E., Zha, Y., Sweis, R. F., & Gajewski, T. F. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114141 · Cited by 31
Modeling T cell temporal response to cancer immunotherapy rationalizes development of combinatorial treatment protocols
Barboy, O., Bercovich, A., Li, H., Eyal-Lubling, Y., Yalin, A., Itai, Y. S., Abadie, K., Zada, M., David, E., Shlomi-Loubaton, S., et al. (2024) · Nature Cancer · doi:10.1038/s43018-024-00734-z · Cited by 32
“To examine the applicability of the inferred anti-PD-1 mechanism of action from mouse models to T cell dynamics in human tumors, we reanalyzed a window-of-opportunity cohort of 31 patients with breast cancer 27 .”
A single-cell map of peripheral alterations after FMT treatment in patients with systemic lupus erythematosus
Zheng, M., Zhou, W., Huang, C., Hu, Z. Q., Zhang, B., Lu, Q., & Zhao, M. (2023) · Journal of Autoimmunity · doi:10.1016/j.jaut.2022.102989 · Cited by 29
Single‐Nucleus and Spatial Transcriptome Profiling Delineates the Multicellular Ecosystem in Hepatocellular Carcinoma After Hepatic Arterial Infusion Chemotherapy
Huang, Y., Du, Z., Lai, Z., Wen, D., Huang, L., He, M., Wu, Z., Li, H., OuYang, H., Wu, W., et al. (2024) · Advanced Science · doi:10.1002/advs.202405749 · Cited by 25
Dual TLR9 and PD-L1 targeting unleashes dendritic cells to induce durable antitumor immunity
Fernandez-Rodriguez, L., Cianciaruso, C., Bill, R., Trefny, M. P., Klar, R., Kirchhammer, N., Buchi, M., Festag, J., Michel, S., Köhler, R. H., et al. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2023-006714 · Cited by 28
Stem-like CD8+ T cells in cancer
Steiner, C., Denlinger, N., Huang, X., & Yang, Y. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1426418 · Cited by 28
“Clinical observations have revealed that tumors with such regions correlate with favorable therapeutic responses (51, 59, 71, 87, 88).”
Background
TREM2-mediated regulation of myeloid cells in the tumor microenvironment: new insights and therapeutic prospects
Huang, Y., & Fang, W. (2025) · npj Precision Oncology · doi:10.1038/s41698-025-01152-9 · Cited by 30

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: Bassez, Ayse
Vos, Hanne
Floris, Giuseppe
Arijs, Ingrid
Desmedt, Christine
Boeckx, Bram
Vanden Bempt, Marlies
Nevelsteen, Ines
Punie, Kevin
Neven, Patrick
Garg, Abhishek D.
Wildiers, Hans
Qian, Junbin
Smeets, Ann
Lambrechts, Diether
Venue: Nature Medicine
Publisher: Springer Science and Business Media LLC
Published: 2021-05
Volume: 27
Issue: 5
Pages: 820-832
ISSN: 1078-8956 (ISSN-L)
1546-170X
DOI: 10.1038/s41591-021-01323-8
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: other-oa
www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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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A single-cell map of intratumoral changes during anti-PD1 treatment of patients with breast cancer

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