BIOKEY: A single-cell catalogue of the dynamic changes underlying Checkpoint Immunotherapy response in Early Breast Cancer

Checkpoint immunotherapy combined with neoadjuvant chemotherapy improves complete pathologic response in a subset of breast cancer patients. Here, we applied single-cell profiling to tumor biopsies collected before and during anti-PD1 therapy. One-third of tumors exhibited proliferative T-cells expanding along CD8+ or CD4+ lineages, which were either characterized by increased cytotoxicity and exhaustion or improved T-helper function, respectively. Lineage tracing in non-expanding tumors revealed at which point in the lineage T-cells were impaired, while gene expression modeling along these lineages revealed novel genes and underlying transcription factors involved in T-cell expansion. Interestingly, different dendritic and myeloid cell phenotypes could either stimulate or inhibit expanding T-cells, while cell-to-cell communication revealed an integrated immune context highly predictive of T-cell expansion, consisting of immune-stimulatory/-inhibitory interactions between cancer and various immune cell types. Our data yield unprecedented insights into the dynamic changes underlying checkpoint immunotherapy response in breast cancer.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

4 Datasets 39 Publications

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD00001006608	Single-cell RNA and VDJ sequencing of early breast cancer	Illumina NovaSeq 6000	84
EGAD00001007056	Low-coverage whole genome sequencing of 29 early breast cancer samples.	Illumina HiSeq 4000	29
EGAD00001007057	Whole-exome sequencing of 30 early breast cancer samples.	Illumina HiSeq 4000	30
EGAD00001007058	CITE-seq of early breast cancer samples.	Illumina HiSeq 4000 Illumina NovaSeq 6000	16

Publications	Citations
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Bulk and Single-Cell Profiling of Breast Tumors Identifies TREM-1 as a Dominant Immune Suppressive Marker Associated With Poor Outcomes. Pullikuth AK, Routh ED, Zimmerman KD, Chifman J, Chou JW, Soike MH, Jin G, Su J, Song Q, Black MA, Print C, Bedognetti D, Howard-McNatt M, O'Neill SS, Thomas A, Langefeld CD, Sigalov AB, Lu Y, Miller LD. Front Oncol 11: 2021 734959	28
Neoantigen-specific CD4<sup>+</sup> T cells in human melanoma have diverse differentiation states and correlate with CD8<sup>+</sup> T cell, macrophage, and B cell function. Veatch JR, Lee SM, Shasha C, Singhi N, Szeto JL, Moshiri AS, Kim TS, Smythe K, Kong P, Fitzgibbon M, Jesernig B, Bhatia S, Tykodi SS, Hall ET, Byrd DR, Thompson JA, Pillarisetty VG, Duhen T, McGarry Houghton A, Newell E, Gottardo R, Riddell SR. Cancer Cell 40: 2022 393-409.e9	108
Cancer immunotherapies transition endothelial cells into HEVs that generate TCF1<sup>+</sup> T lymphocyte niches through a feed-forward loop. Hua Y, Vella G, Rambow F, Allen E, Antoranz Martinez A, Duhamel M, Takeda A, Jalkanen S, Junius S, Smeets A, Nittner D, Dimmeler S, Hehlgans T, Liston A, Bosisio FM, Floris G, Laoui D, Hollmén M, Lambrechts D, Merchiers P, Marine JC, Schlenner S, Bergers G. Cancer Cell 40: 2022 1600-1618.e10	112
Integrated Analysis of Single-Cell and Bulk RNA-Sequencing Reveals a Tissue-Resident Macrophage-Related Signature for Predicting Immunotherapy Response in Breast Cancer Patients. Xia ZA, Zhou Y, Li J, He J. Cancers (Basel) 14: 2022 5506	7
The tumor microenvironment and triple-negative breast cancer aggressiveness: shedding light on mechanisms and targeting. Furukawa N, Stearns V, Santa-Maria CA, Popel AS. Expert Opin Ther Targets 26: 2022 1041-1056	13
Orthogonal cytokine engineering enables novel synthetic effector states escaping canonical exhaustion in tumor-rejecting CD8<sup>+</sup> T cells. Corria-Osorio J, Carmona SJ, Stefanidis E, Andreatta M, Ortiz-Miranda Y, Muller T, Rota IA, Crespo I, Seijo B, Castro W, Jimenez-Luna C, Scarpellino L, Ronet C, Spill A, Lanitis E, Romero P, Luther SA, Irving M, Coukos G. Nat Immunol 24: 2023 869-883	36
Pan-cancer T cell atlas links a cellular stress response state to immunotherapy resistance. Chu Y, Dai E, Li Y, Han G, Pei G, Ingram DR, Thakkar K, Qin JJ, Dang M, Le X, Hu C, Deng Q, Sinjab A, Gupta P, Wang R, Hao D, Peng F, Yan X, Liu Y, Song S, Zhang S, Heymach JV, Reuben A, Elamin YY, Pizzi MP, Lu Y, Lazcano R, Hu J, Li M, Curran M, Futreal A, Maitra A, Jazaeri AA, Ajani JA, Swanton C, Cheng XD, Abbas HA, Gillison M, Bhat K, Lazar AJ, Green M, Litchfield K, Kadara H, Yee C, Wang L. Nat Med 29: 2023 1550-1562	260
CD25high Effector Regulatory T Cells Hamper Responses to PD-1 Blockade in Triple-Negative Breast Cancer. Fattori S, Le Roy A, Houacine J, Robert L, Abes R, Gorvel L, Granjeaud S, Rouvière MS, Ben Amara A, Boucherit N, Tarpin C, Pakradouni J, Charafe-Jauffret E, Houvenaeghel G, Lambaudie E, Bertucci F, Rochigneux P, Gonçalves A, Foussat A, Chrétien AS, Olive D. Cancer Res 83: 2023 3026-3044	15
Obesity-associated changes in molecular biology of primary breast cancer. Nguyen HL, Geukens T, Maetens M, Aparicio S, Bassez A, Borg A, Brock J, Broeks A, Caldas C, Cardoso F, De Schepper M, Delorenzi M, Drukker CA, Glas AM, Green AR, Isnaldi E, Eyfjörð J, Khout H, Knappskog S, Krishnamurthy S, Lakhani SR, Langerod A, Martens JWM, McCart Reed AE, Murphy L, Naulaerts S, Nik-Zainal S, Nevelsteen I, Neven P, Piccart M, Poncet C, Punie K, Purdie C, Rakha EA, Richardson A, Rutgers E, Vincent-Salomon A, Simpson PT, Schmidt MK, Sotiriou C, Span PN, Tan KTB, Thompson A, Tommasi S, Van Baelen K, Van de Vijver M, Van Laere S, Van't Veer L, Viale G, Viari A, Vos H, Witteveen AT, Wildiers H, Floris G, Garg AD, Smeets A, Lambrechts D, Biganzoli E, Richard F, Desmedt C. Nat Commun 14: 2023 4418	32
The expression profiles of signature genes from CD103<sup>+</sup>LAG3<sup>+</sup> tumour-infiltrating lymphocyte subsets predict breast cancer survival. Xia ZA, Lu C, Pan C, Li J, Li J, Mao Y, Sun L, He J. BMC Med 21: 2023 268	8
Performance of tumour microenvironment deconvolution methods in breast cancer using single-cell simulated bulk mixtures. Tran KA, Addala V, Johnston RL, Lovell D, Bradley A, Koufariotis LT, Wood S, Wu SZ, Roden D, Al-Eryani G, Swarbrick A, Williams ED, Pearson JV, Kondrashova O, Waddell N. Nat Commun 14: 2023 5758	35
Supervised discovery of interpretable gene programs from single-cell data. Kunes RZ, Walle T, Land M, Nawy T, Pe'er D. Nat Biotechnol 42: 2024 1084-1095	50
Sex disparities revealed by single-cell and bulk sequencing and their impacts on the efficacy of immunotherapy in esophageal cancer. Yan H, Huang J, Li Y, Zhao B. Biol Sex Differ 15: 2024 22	6
A Subpopulation of Luminal Progenitors Secretes Pleiotrophin to Promote Angiogenesis and Metastasis in Inflammatory Breast Cancer. Zhang M, Zhou K, Wang Z, Liu T, Stevens LE, Lynce F, Chen WY, Peng S, Xie Y, Zhai D, Chen Q, Shi Y, Shi H, Yuan Z, Li X, Xu J, Cai Z, Guo J, Shao N, Lin Y. Cancer Res 84: 2024 1781-1798	8
Unleashing Natural IL18 Activity Using an Anti-IL18BP Blocker Induces Potent Immune Stimulation and Antitumor Effects. Menachem A, Alteber Z, Cojocaru G, Fridman Kfir T, Blat D, Leiderman O, Galperin M, Sever L, Cohen N, Cohen K, Granit RZ, Vols S, Frenkel M, Soffer L, Meyer K, Menachem K, Galon Tilleman H, Morein D, Borukhov I, Toporik A, Perpinial Shahor M, Tatirovsky E, Mizrachi A, Levy-Barda A, Sadot E, Strenov Y, Eitan R, Jakobson-Setton A, Yanichkin N, Ferre P, Ophir E. Cancer Immunol Res 12: 2024 687-703	10
C5aR1 inhibition reprograms tumor associated macrophages and reverses PARP inhibitor resistance in breast cancer. Li X, Poire A, Jeong KJ, Zhang D, Ozmen TY, Chen G, Sun C, Mills GB. Nat Commun 15: 2024 4485	11
Identification of Hypoxia-ALCAM<sup>high</sup> 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, Lin C, Hu Q, Ye Y, Han L. Adv Sci (Weinh) 11: 2024 e2309885	12
Progestogen-driven B7-H4 contributes to onco-fetal immune tolerance. Yu J, Yan Y, Li S, Xu Y, Parolia A, Rizvi S, Wang W, Zhai Y, Xiao R, Li X, Liao P, Zhou J, Okla K, Lin H, Lin X, Grove S, Wei S, Vatan L, Hu J, Szumilo J, Kotarski J, Freeman ZT, Skala S, Wicha M, Cho KR, Chinnaiyan AM, Schon S, Wen F, Kryczek I, Wang S, Chen L, Zou W. Cell 187: 2024 4713-4732.e19	19
Single-cell resolution characterization of myeloid-derived cell states with implication in cancer outcome. Guimarães GR, Maklouf GR, Teixeira CE, de Oliveira Santos L, Tessarollo NG, de Toledo NE, Serain AF, de Lanna CA, Pretti MA, da Cruz JGV, Falchetti M, Dimas MM, Filgueiras IS, Cabral-Marques O, Ramos RN, de Macedo FC, Rodrigues FR, Bastos NC, da Silva JL, Lummertz da Rocha E, Chaves CBP, de Melo AC, Moraes-Vieira PMM, Mori MA, Boroni M. Nat Commun 15: 2024 5694	27
Deciphering breast cancer dynamics: insights from single-cell and spatial profiling in the multi-omics era. Xiong X, Wang X, Liu CC, Shao ZM, Yu KD. Biomark Res 12: 2024 107	4
Multiomics and single-cell sequencings reveal the specific biological characteristics of low Ki-67 triple-negative breast cancer. Han B, Han X, Luo H, Nasir J, Chen C, Shao Z, Ling H, Hu X. Cancer Innov 3: 2024 e146	0
T Cells Instruct Immune Checkpoint Inhibitor Therapy Resistance in Tumors Responsive to IL1 and TNFα Inflammation. Cho NW, Guldberg SM, Nabet BY, Yu JZ, Kim EJ, Hiam-Galvez KJ, Yee JL, DeBarge R, Tenvooren I, Ashitey NA, Lynce F, Dillon DA, Rosenbluth JM, Spitzer MH. Cancer Immunol Res 13: 2025 229-244	6
Immunosuppressive microenvironment of liver restrains chemotherapeutic efficacy in triple-negative breast cancer. Liu M, Qian M, Sun W, Sun X, Sun Y, Yu M, Tang X, Mao X, Sun C, Qi Q, Zhang W, Ling P, Pang Z, Li W, Pan H, Wang S, Zhou W. J Immunother Cancer 13: 2025 e010871	2
Deciphering immune predictors of immunotherapy response: A multiomics approach at the pan-cancer level. Li X, Pan L, Li W, Liu B, Xiao C, Chew V, Zhang X, Long W, Ginhoux F, Loscalzo J, Buggert M, Zhang X, Sheng R, Wang Z. Cell Rep Med 6: 2025 101992	4
Targeting tumor-intrinsic S100 calcium-binding protein A1 augments antitumor immunity and potentiates immunotherapy efficacy. Guo Y, Wan R, Duan J, Yuan L, Wang Z, Zhong J, Zhang X, Ma Z, Bai H, Wang J. Signal Transduct Target Ther 10: 2025 99	2
Single-cell and multi-omics integration reveals cholesterol biosynthesis as a synergistic target with HER2 in aggressive breast cancer. Tseng TY, Hsieh CH, Liu JY, Huang HC, Juan HF. Comput Struct Biotechnol J 27: 2025 1719-1731	0
Serotonin transporter inhibits antitumor immunity through regulating the intratumoral serotonin axis. Li B, Elsten-Brown J, Li M, Zhu E, Li Z, Chen Y, Kang E, Ma F, Chiang J, Li YR, Zhu Y, Huang J, Fung A, Scarborough Q, Cadd R, Zhou JJ, Chin AI, Pellegrini M, Yang L. Cell 188: 2025 3823-3842.e21	13
Dual ENPP1/ATM depletion blunts DNA damage repair boosting radioimmune efficacy to abrogate triple-negative breast cancer. Ruiz-Fernández de Córdoba B, Valencia K, Welch C, Moreno H, Martínez-Canarias S, Zandueta C, Gómez E, Calvo A, Otegui N, Echepare M, Garzón I, Ajona D, Lara-Astiaso D, Guruceaga E, Guembe L, Pío R, Melero I, Vicent S, Pastor F, Martínez-Monge R, Lecanda F. Signal Transduct Target Ther 10: 2025 185	1
AAnet Resolves a Continuum of Spatially Localized Cell States to Unveil Intratumoral Heterogeneity. Venkat A, Youlten SE, San Juan BP, Purcell CA, Gupta S, Amodio M, Neumann DP, Lock JG, Westacott AE, McCool CS, Burkhardt DB, Benz A, Mollbrink A, Lundeberg J, van Dijk D, Holst J, Goldstein LD, Kummerfeld S, Krishnaswamy S, Chaffer CL. Cancer Discov 15: 2025 2139-2165	1
Modeling tumor relapse using proliferation tracing and ablation transgenic mouse. Zhao C, Zheng XN, Huang HY, Tian L. NPJ Breast Cancer 11: 2025 73	1
Identification of breast cancer subtypes and drug response prediction through forward and reverse translation. Karam J, Rejto PA, Bienkowska JR, Mu XJ, Roh W. NPJ Precis Oncol 9: 2025 267	0
Lipid nanoparticle-delivered IFNα2 activates Cxcl9 to increase T cell tumor recruitment to suppress lung metastasis. Fick K, Kerns N, Zhao Y, Tiamiyu Z, Poschel D, Czabala P, Yang D, Tang Y, Xie J, Fesenkova V, Pacholczyk R, Shi H, Liu K, Redd PS. J Immunother Cancer 13: 2025 e011415	1
Modulation of fibronectin extracellular matrix enhances anti-tumor efficacy of immune checkpoint blockade. Khan KA, Caunt Mitzner M, Cruz-Munoz W, Li G, Himmels P, Xu P, Kuo HY, Jesudason R, Gogineni A, Weimer R, Chow A, Piskol R, Michael IP, Ye W, Kerbel RS. Cell Rep Med 6: 2025 102322	0
Gene Signature-Based Drug Screening Reveals Ponatinib Enhances Immunotherapy Efficacy in Triple-Negative Breast Cancer by Reversing MDSC-Mediated Immunosuppressive Tumor Microenvironment. Wang Q, Li S, Wu Y, Yu X, Dai Y, Wang Y, Li L, Yang M, Lin K, Shao W, Wang H, Wang H, Zhang G, Wang D. Research (Wash D C) 8: 2025 0915	0
A pan-immunotherapy signature to predict intratumoral CD8<sup>+</sup> T cell expansions. Takahashi M, Tsunoda M, Aoki H, Kurosu M, Ogiwara H, Shichino S, Bending D, Ishikawa S, Thaventhiran JED, Matsushima K, Ueha S. Nat Commun 16: 2025 9175	0
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