Single-cell meta-analyses reveal responses of tumor-reactive CXCL13+ T cells to immune-checkpoint blockade
Abstract
Immune-checkpoint blockade (ICB) therapies represent a paradigm shift in the treatment of human cancers; however, it remains incompletely understood how tumor-reactive T cells respond to ICB across tumor types. Here, we demonstrate that measuring CXCL13 expression could effectively identify both precursor and terminally differentiated tumor-reactive CD8+ T cells within tumors. Applying this approach, we performed meta-analyses of published single-cell data for CXCL13+CD8+ T cells in 225 samples from 102 patients treated with ICB across five cancer types. We found that CXCL13+CD8+ T cells were correlated with favorable responses to ICB, and the treatment further increased such cells in responsive tumors. In addition, CXCL13+ tumor-reactive subsets exhibited variable responses to ICB in distinct contexts, likely due to different degrees of exhaustion-related immunosuppression. Our integrated analyses provide insights into mechanisms underlying ICB and suggest that bolstering precursor tumor-reactive CD8+ T cells might provide an effective therapeutic approach to improve cancer treatment.
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Analysis of published single-cell transcriptomics, epigenomics and TCR data found that the presence of CXCL13+CD8+ T cells correlated with favourable response to ICB across different tumour types.
“One study resolved how tumour-reactive T cells respond to ICB in different tumour types by analysing previously published single-cell transcriptomics, epigenomics and TCR data, finding that the presence CXCL13+CD8+ T cells correlated with favourable response to ICB164.”
From The technological landscape and applications of single-cell multi-omics (2023) · cites this paper as [164]
Cites
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)
Eisenhauer, E. A., Therasse, P., Bogaerts, J., Schwartz, L. H., Sargent, D., Ford, R., Dancey, J., Arbuck, S., Gwyther, S., Mooney, M., et al. (2009) · European Journal of Cancer · doi:10.1016/j.ejca.2008.10.026 · Cited by 29,534 · see citing works
Comprehensive Integration of Single-Cell Data
Stuart, T., Butler, A., Hoffman, P., Hafemeister, C., Papalexi, E., Mauck, W. M., Hao, Y., Stoeckius, M., Smibert, P., & Satija, R. (2019) · Cell · doi:10.1016/j.cell.2019.05.031 · Cited by 15,453 · see citing works
SCANPY: large-scale single-cell gene expression data analysis
Wolf, F. A., Angerer, P., & Theis, F. J. (2018) · Genome Biology · doi:10.1186/s13059-017-1382-0 · Cited by 8,881 · see citing works
Oncology meets immunology: the cancer-immunity cycle.
Chen, D. S., & Mellman, I. (2013) · Immunity · doi:10.1016/j.immuni.2013.07.012 · Cited by 6,929 · see citing works
The future of immune checkpoint therapy
Sharma, P., & Allison, J. P. (2015) · Science · doi:10.1126/science.aaa8172 · Cited by 4,878 · see citing works
La Manno, G., Soldatov, R., Zeisel, A., Braun, E., Hochgerner, H., Petukhov, V., Lidschreiber, K., Kastriti, M. E., Lönnerberg, P., Furlan, A., et al. (2018) · Nature · doi:10.1038/s41586-018-0414-6 · Cited by 4,118 · see citing works
Tumor mutational burden and response rate to PD-1 inhibition
Yarchoan, M., Hopkins, A., & Jaffee, E. M. (2017) · New England Journal of Medicine · doi:10.1056/nejmc1713444 · Cited by 3,230 · see citing works
Generalizing RNA velocity to transient cell states through dynamical modeling
Bergen, V., Lange, M., Peidli, S., Wolf, F. A., & Theis, F. J. (2020) · Nature Biotechnology · doi:10.1038/s41587-020-0591-3 · Cited by 2,951 · see citing works
Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy
Im, S. J., Hashimoto, M., Gerner, M. Y., Lee, J., Kissick, H. T., Burger, M. C., Shan, Q., Hale, J. S., Lee, J., Nasti, T. H., et al. (2016) · Nature · doi:10.1038/nature19330 · Cited by 2,070 · see citing works
CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer
McLane, L. M., Abdel-Hakeem, M. S., & Wherry, E. J. (2019) · Annual Review of Immunology · doi:10.1146/annurev-immunol-041015-055318 · Cited by 1,973 · see citing works
Ahmadzadeh, M., Johnson, L. A., Heemskerk, B., Wunderlich, J. R., Dudley, M. E., White, D. E., & Rosenberg, S. A. (2009) · Blood · doi:10.1182/blood-2008-12-195792 · Cited by 1,766 · see citing works
Harding, F., McArthur, J. G., Gross, J. A., Raulet, D. H., & Allison, J. P. (1992) · Nature · doi:10.1038/356607a0 · Cited by 1,558 · see citing works
Clonal replacement of tumor-specific T cells following PD-1 blockade
Yost, K. E., Satpathy, A. T., Wells, D. K., Qi, Y., Wang, C., Kageyama, R., McNamara, K. L., Granja, J. M., Sarin, K. Y., Brown, R. A., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0522-3 · Cited by 1,534 · see citing works
Lineage tracking reveals dynamic relationships of T cells in colorectal cancer
Zhang, L., Yu, X., Zheng, L., Zhang, Y., Li, Y., Fang, Q., Gao, R., Kang, B., Zhang, Q., Huang, J. Y., et al. (2018) · Nature · doi:10.1038/s41586-018-0694-x · Cited by 1,505 · see citing works
Self-citationCD8+ T cell states in human cancer: insights from single-cell analysis
van der Leun, A. M., Thommen, D. S., & Schumacher, T. N. (2020) · Nature reviews. Cancer · doi:10.1038/s41568-019-0235-4 · Cited by 1,439 · see citing works
A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade
Jerby-Arnon, L., Shah, P., Cuoco, M. S., Rodman, C., Su, M.-J., Melms, J. C., Leeson, R., Kanodia, A., Mei, S., Lin, J.-R., et al. (2018) · Cell · doi:10.1016/j.cell.2018.09.006 · Cited by 1,429 · see citing works
Pan-cancer single-cell landscape of tumor-infiltrating T cells
Zheng, L., Qin, S., Si, W., Wang, A., Xing, B., Gao, R., Ren, X., Wang, L., Wu, X., Zhang, J., et al. (2021) · Science · doi:10.1126/science.abe6474 · Cited by 1,402 · see citing works
Self-citationBystander CD8+ T cells are abundant and phenotypically distinct in human tumour infiltrates
Simoni, Y., Becht, E., Fehlings, M., Loh, C. Y., Koo, S.-L., Teng, K. W. W., Yeong, J. P. S., Nahar, R., Zhang, T., Kared, H., et al. (2018) · Nature · doi:10.1038/s41586-018-0130-2 · Cited by 1,370 · see citing works
Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade
Wei, S. C., Levine, J. H., Cogdill, A. P., Zhao, Y., Anang, N.-A. A. S., Andrews, M. C., Sharma, P., Wang, J., Wargo, J. A., Pe’er, D., et al. (2017) · Cell · doi:10.1016/j.cell.2017.07.024 · Cited by 1,302 · see citing works
Thommen, D. S., Koelzer, V. H., Herzig, P., Roller, A., Trefny, M., Dimeloe, S., Kiialainen, A., Hanhart, J., Schill, C., Hess, C., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0057-z · Cited by 1,161 · see citing works
Li, H., van der Leun, A. M., Yofe, I., Lubling, Y., Gelbard-Solodkin, D., van Akkooi, A. C. J., van den Braber, M., Rozeman, E. A., Haanen, J. B. A. G., Blank, C. U., et al. (2019) · Cell · doi:10.1016/j.cell.2018.11.043 · Cited by 1,101 · see citing works
Beltra, J., Manne, S., Abdel-Hakeem, M. S., Kurachi, M., Giles, J. R., Chen, Z., Casella, V., Ngiow, S. F., Khan, O., Huang, Y., et al. (2020) · Immunity · doi:10.1016/j.immuni.2020.04.014 · Cited by 1,091 · see citing works
Braun, D. A., Hou, Y., Bakouny, Z., Ficial, M., Sant’ Angelo, M., Forman, J., Ross-Macdonald, P., Berger, A. C., Jegede, O. A., Elagina, L., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0839-y · Cited by 992 · see citing works
Hellmann, M. D., Rizvi, N. A., Goldman, J. W., Gettinger, S. N., Borghaei, H., Brahmer, J. R., Ready, N. E., Gerber, D. E., Chow, L. Q., Juergens, R. A., et al. (2017) · The Lancet Oncology · doi:10.1016/s1470-2045(16)30624-6 · Cited by 962 · see citing works
Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors
Duhen, T., Duhen, R., Montler, R., Moses, J., Moudgil, T., de Miranda, N. F., Goodall, C. P., Blair, T. C., Fox, B. A., McDermott, J. E., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05072-0 · Cited by 938 · see citing works
BBKNN: fast batch alignment of single cell transcriptomes
Polański, K., Young, M. D., Miao, Z., Meyer, K. B., Teichmann, S. A., & Park, J.-E. (2020) · Bioinformatics · doi:10.1093/bioinformatics/btz625 · Cited by 932 · see citing works
Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3
Wang, J., Sanmamed, M. F., Datar, I. J., Su, T. T., Ji, L., Sun, J., Chen, L., Chen, Y., Zhu, G., Yin, W., et al. (2018) · Cell · doi:10.1016/j.cell.2018.11.010 · Cited by 879 · see citing works
A single-cell map of intratumoral changes during anti-PD1 treatment of patients with breast cancer
Bassez, A., Vos, H., Van Dyck, L., Floris, G., Arijs, I., Desmedt, C., Boeckx, B., Vanden Bempt, M., Nevelsteen, I., Lambein, K., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01323-8 · Cited by 867 · see citing works
Matsuzaki, J., Gnjatic, S., Mhawech-Fauceglia, P., Beck, A., Miller, A., Tsuji, T., Eppolito, C., Qian, F., Lele, S., Shrikant, P., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1003345107 · Cited by 859 · see citing works
Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patients
Baitsch, L., Baumgaertner, P., Devêvre, E., Raghav, S. K., Legat, A., Barba, L., Wieckowski, S., Bouzourene, H., Deplancke, B., Romero, P., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci46102 · Cited by 845 · see citing works
Zhang, Y., Chen, H., Mo, H., Hu, X., Gao, R., Zhao, Y., Liu, B., Niu, L., Sun, X., Yu, X., et al. (2021) · Cancer Cell · doi:10.1016/j.ccell.2021.09.010 · Cited by 783 · see citing works
Self-citationCEACAM1 regulates TIM-3-mediated tolerance and exhaustion
Huang, Y.-H., Zhu, C., Kondo, Y., Anderson, A. C., Gandhi, A., Russell, A., Dougan, S. K., Petersen, B.-S., Melum, E., Pertel, T., et al. (2015) · Nature · doi:10.1038/nature13848 · Cited by 717 · see citing works
The PD-1/PD-L1-Checkpoint Restrains T cell Immunity in Tumor-Draining Lymph Nodes
Dammeijer, F. F., van Gulijk, M., Mulder, E. E. A. P., Lukkes, M. M., Klaase, L., van den Bosch, T. P. P., van Nimwegen, M., Lau, S. P., Latupeirissa, K., Schetters, S. T. T., et al. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.09.001 · Cited by 701 · see citing works
Hudson, W. H., Gensheimer, J., Hashimoto, M., Wieland, A., Valanparambil, R. M., Li, P., Lin, J.-X., Konieczny, B. T., Im, S. J., Freeman, G. J., et al. (2019) · Immunity · doi:10.1016/j.immuni.2019.11.002 · Cited by 656 · see citing works
Tumor and immune reprogramming during immunotherapy in advanced renal cell carcinoma
Bi, K., He, M. X., Bakouny, Z., Kanodia, A., Napolitano, S., Wu, J., Grimaldi, G., Braun, D. A., Cuoco, M. S., Mayorga, A., et al. (2021) · Cancer Cell · doi:10.1016/j.ccell.2021.02.015 · Cited by 613 · see citing works
Immune checkpoint blockade in infectious diseases
Wykes, M., & Lewin, S. R. (2017) · Nature reviews. Immunology · doi:10.1038/nri.2017.112 · Cited by 569 · see citing works
Phenotype, specificity and avidity of antitumour CD8+ T cells in melanoma
Oliveira, G., Stromhaug, K., Klaeger, S., Kula, T., Frederick, D. T., Le, P. M., Forman, J., Huang, T., Li, S., Zhang, W., et al. (2021) · Nature · doi:10.1038/s41586-021-03704-y · Cited by 563 · see citing works
PD-L1 expression and tumor mutational burden are independent biomarkers in most cancers
Yarchoan, M. M., Albacker, L. A., Hopkins, A. C., Montesion, M., Murugesan, K., Vithayathil, T., Zaidi, N., Azad, N. S., Laheru, D. A., Frampton, G. M., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.126908 · Cited by 554 · see citing works
Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers
Caushi, J. X., Zhang, J., Ji, Z., Vaghasia, A. M., Zhang, B., Hsiue, E. H.-C., Mog, B. J., Hou, W., Justesen, S. F. L., Blosser, R. L., et al. (2021) · Nature · doi:10.1038/s41586-021-03752-4 · Cited by 539 · see citing works
Linking T-cell receptor sequence to functional phenotype at the single-cell level
Han, A. S., Glanville, J., Hansmann, L., & Davis, M. M. (2014) · Nature Biotechnology · doi:10.1038/nbt.2938 · Cited by 534 · see citing works
Liu, B., Hu, X., Feng, K., Gao, R., Xue, Z., Zhang, S., Zhang, Y., Corse, E., Hu, Y., Han, W., et al. (2021) · Nature Cancer · doi:10.1038/s43018-021-00292-8 · Cited by 473 · see citing works
Self-citationMolecular signatures of antitumor neoantigen-reactive T cells from metastatic human cancers
Lowery, F. J., Krishna, S., Yossef, R., Parikh, N. B., Chatani, P. D., Zacharakis, N., Parkhurst, M. R., Levin, N., Sindiri, S., Sachs, A., et al. (2022) · Science · doi:10.1126/science.abl5447 · Cited by 453 · see citing works
Krishna, C., DiNatale, R. G., Kuo, F., Srivastava, R. M., Vuong, L. H., Chowell, D., Gupta, S., Vanderbilt, C., Purohit, T. A., Liu, M., et al. (2021) · Cancer Cell · doi:10.1016/j.ccell.2021.03.007 · Cited by 427 · see citing works
Connolly, K. A., Kuchroo, M. R., Venkat, A., Khatun, A., Wang, J., William, I., Hornick, N. I., Fitzgerald, B., Damo, M., Kasmani, M. Y., et al. (2021) · Science Immunology · doi:10.1126/sciimmunol.abg7836 · Cited by 403 · see citing works
<i>Nebulosa</i> recovers single-cell gene expression signals by kernel density estimation
Alquicira-Hernandez, J., & Powell, J. E. (2021) · Bioinformatics · doi:10.1093/bioinformatics/btab003 · Cited by 381 · see citing works
Functional HPV-specific PD-1+ stem-like CD8 T cells in head and neck cancer
Eberhardt, C. S., Kissick, H. T., Patel, M. R., Cardenas, M. A., Prokhnevska, N., Obeng, R. C., Nasti, T. H., Griffith, C. C., Im, S. J., Wang, X., et al. (2021) · Nature · doi:10.1038/s41586-021-03862-z · Cited by 336 · see citing works
Workel, H. H., Lubbers, J. M., Arnold, R. R., Prins, T. M., van der Vlies, P., de Lange, K., Bosse, T., van Gool, I. C., Eggink, F. A., Wouters, M. C. A., et al. (2019) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-18-0517 · Cited by 258 · see citing works
Immune awakening revealed by peripheral T cell dynamics after one cycle of immunotherapy
Valpione, S., Galvani, E., Tweedy, J., Mundra, P. A., Banyard, A., Middlehurst, P., Barry, J., Mills, S. C., Salih, Z., Weightman, J., et al. (2020) · Nature Cancer · doi:10.1038/s43018-019-0022-x · Cited by 216 · see citing works
An entropy-based metric for assessing the purity of single cell populations
Liu, B., Li, C., Li, Z., Wang, D., Ren, X., & Zhang, Z. (2020) · Nature Communications · doi:10.1038/s41467-020-16904-3 · Cited by 213 · see citing works
Self-citationAn expanded universe of cancer targets
Hahn, W. C., Bader, J. S., Braun, T. P., Califano, A., Clemons, P. A., Druker, B. J., Ewald, A. J., Fu, H., Jagu, S., Kemp, C. J., et al. (2021) · Cell · doi:10.1016/j.cell.2021.02.020 · Cited by 213 · see citing works
Cohen, M., Giladi, A., Barboy, O., Hamon, P., Li, B.-G., Zada, M., Gurevich-Shapiro, A., Beccaria, C., David, E., Maier, B., et al. (2022) · Nature Cancer · doi:10.1038/s43018-022-00338-5 · Cited by 181 · see citing works
SciBet as a portable and fast single cell type identifier
Li, C., Liu, B., Kang, B., Liu, Z., Liu, Y., Chen, C., Ren, X., & Zhang, Z. (2020) · Nature Communications · doi:10.1038/s41467-020-15523-2 · Cited by 177 · see citing works
Self-citationClonal replacement of tumor-specific T cells following PD-1 blockadePreprint
Yost, K. E., Satpathy, A. T., Wells, D. K., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/648899 · Cited by 163 · see citing works
Transcriptomic profiles of neoantigen-reactive T cells in human gastrointestinal cancers
Zheng, C., Fass, J. N., Shih, Y.-P., Gunderson, A. J., Silva, N. S., Huang, H., Bernard, B. M., Rajamanickam, V., Slagel, J., Bifulco, C. B., et al. (2022) · Cancer Cell · doi:10.1016/j.ccell.2022.03.005 · Cited by 143 · see citing works
Muthuswamy, R., Berk, E., Junecko, B. A. F., Zeh, H. J., Zureikat, A. H., Normolle, D. P., Luong, T. M., Reinhart, T. A., Bartlett, D. L., & Kaliński, P. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-4136 · Cited by 139 · see citing works
Palmer, A. C., Izar, B., Hwangbo, H., & Sorger, P. K. (2022) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-2275 · Cited by 84 · see citing works
Shen, M., Smith, H. A., Wei, Y., et al. (2021) · Nature Cancer · doi:10.1038/s43018-021-00280-y · Cited by 81 · see citing works
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The technological landscape and applications of single-cell multi-omics
Baysoy, A., Bai, Z., Satija, R., & Fan, R. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-023-00615-w · Cited by 1,037 · see citing works
Magen, A., Hamon, P., Fiaschi, N., Soong, B. Y., Park, M. D., Mattiuz, R., Humblin, E., Troncoso, L., D’souza, D., Dawson, T., et al. (2023) · Nature Medicine · doi:10.1038/s41591-023-02345-0 · Cited by 429 · see citing works
Guo, X., Nie, H., Zhang, W., Li, J., Ge, J., Xie, B., Hu, W., Zhu, Y., Zhong, N., Zhang, X., et al. (2025) · Cancer Cell · doi:10.1016/j.ccell.2025.01.001 · Cited by 100 · see citing works
Sakai, S. A., Oyoshi, H., Nakamura, M., Taki, T., Nomura, K., Hojo, H., Hirata, H., Motegi, A., Nakamura, Y., Zenkoh, J., et al. (2025) · British Journal of Cancer · doi:10.1038/s41416-025-03088-0 · Cited by 15 · see citing works
- Authors
- Liu, B., Zhang, Y., Wang, D., Hu, X., & Zhang, Z.
- Affiliations
- Peking University (CN)
- Analytical Biosciences (China) (CN)
- Corresponding author
- Zhang, Zemin
- Venue
- Nature Cancer
- Published
- 2022-09-22
- Volume
- 3
- Issue
- 9
- Pages
- 1123-1136
- ISSN
- 2662-1347 (ISSN-L)
- OpenAlex
- W4296694188
- Cited by
- 309
- References
- 57
- Citations by year
- 2026: 63 · 2025: 83 · 2024: 95 · 2023: 65 · 2022: 3
- FWCI
- 25.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Cancer (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- immune checkpoint blockade, CXCL13, CD8+ T cells, tumor-reactive T cells, T cell exhaustion, immunotherapy response, CD4+ T cells, cancer immunotherapy
- MeSH terms
- Immune Checkpoint Inhibitors, Humans, Immunotherapy, Neoplasms, CD8-Positive T-Lymphocytes, Chemokine CXCL13, Single-Cell Analysis, Tumor Microenvironment
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