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Cited by 68Immunotherapy and Immune ResponsesVirus-based gene therapy researchCancer Immunotherapy and Biomarkers

An oncolytic virus delivering tumor-irrelevant bystander T cell epitopes induces anti-tumor immunity and potentiates cancer immunotherapy

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Chen, Xiangyu, Zhao, Jing, Yue, Shuai, Li, Ziyu, Duan, Xiang, Lin, Yao, Yang, Yang, He, Junjian +23 more·2024·Nature Cancer
DOI 10.1038/s43018-024-00760-xPMC PMC11286533
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Abstract

Tumor-specific T cells are crucial in anti-tumor immunity and act as targets for cancer immunotherapies. However, these cells are numerically scarce and functionally exhausted in the tumor microenvironment (TME), leading to inefficacious immunotherapies in most patients with cancer. By contrast, emerging evidence suggested that tumor-irrelevant bystander T (T BYS) cells are abundant and preserve functional memory properties in the TME. To leverage T BYS cells in the TME to eliminate tumor cells, we engineered oncolytic virus (OV) encoding T BYS epitopes (OV-BYTE) to redirect the antigen specificity of tumor cells to pre-existing T BYS cells, leading to effective tumor inhibition in multiple preclinical models. Mechanistically, OV-BYTE induced epitope spreading of tumor antigens to elicit more diverse tumor-specific T cell responses. Remarkably, the OV-BYTE strategy targeting human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell memory efficiently inhibited tumor progression in a human tumor cell-derived xenograft model, providing important insights into the improvement of cancer immunotherapies in a large population with a history of SARS-CoV-2 infection or coronavirus disease 2019 (COVID-19) vaccination.

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  • A recent mouse study reports the anti-tumor activities of pre-existing virus-specific Tem cells.

    “A recent mouse study reports the anti-tumor activities of pre-existing virus-specific Tem cells.81”

    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 [81]

    The Results section (‘OV-BYTE promotes in situ TBYS cells to restrain tumor growth’; page unavailable) reports better tumor control in mice whose tumors contained pre-existing LCMV-specific T cells. This supports the anti-tumor activity of pre-existing virus-specific memory T cells, but the paper does not identify those cells specifically as effector-memory (Tem) cells. (LLM, conf=0.82)

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References 64 · Cited by 68

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  1. [2]McLane, L. M., Abdel-Hakeem, M. S. & Wherry, E. J. CD8 T cell exhaustion during chronic viral infection and cancer. Annu. Rev. Immunol. 37, 457–495 (2019). 30676822
  2. [3]Sun, C., Mezzadra, R. & Schumacher, T. N. Regulation and function of the PD-L1 checkpoint. Immunity 48, 434–452 (2018). 29562194 PMC7116507
  3. [4]Huang, A. C. et al. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 545, 60–65 (2017). 28397821 PMC5554367
  4. [7]Lowery, F. J. et al. Molecular signatures of antitumor neoantigen-reactive T cells from metastatic human cancers. Science 375, 877–884 (2022). 35113651 PMC8996692
  5. [8]Meier, S. L., Satpathy, A. T. & Wells, D. K. Bystander T cells in cancer immunology and therapy. Nat. Cancer 3, 143–155 (2022). 35228747
  6. [9]Oliveira, G. et al. Phenotype, specificity and avidity of antitumour CD8 + T cells in melanoma. Nature 596, 119–125 (2021). 34290406 PMC9187974
  7. [10]Rosato, P. C. et al. Virus-specific memory T cells populate tumors and can be repurposed for tumor immunotherapy. Nat. Commun. 10, 567 (2019). 30718505 PMC6362136
  8. [11]Scheper, W. et al. Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers. Nat. Med. 25, 89–94 (2019). 30510250
  9. [13]Li, S. et al. Bystander CD4 + T cells infiltrate human tumors and are phenotypically distinct. Oncoimmunology 11, 2012961 (2020). PMC9746624 36524209
  10. [14]Caushi, J. X. et al. Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers. Nature 596, 126–132 (2021). 34290408 PMC8338555
  11. [15]Duhen, T. et al. Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors. Nat. Commun. 9, 2724 (2018). 30006565 PMC6045647
  12. [16]Kaufman, H. L., Kohlhapp, F. J. & Zloza, A. Oncolytic viruses: a new class of immunotherapy drugs. Nat. Rev. Drug Discov. 14, 642–662 (2015). 26323545 PMC7097180
  13. [17]Melcher, A., Harrington, K. & Vile, R. Oncolytic virotherapy as immunotherapy. Science 374, 1325–1326 (2021). 34882456 PMC8961675
  14. [18]Todo, T. et al. Intratumoral oncolytic herpes virus G47∆ for residual or recurrent glioblastoma: a phase 2 trial. Nat. Med. 28, 1630–1639 (2022). 35864254 PMC9388376
  15. [20]Alfei, F. et al. TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature 571, 265–269 (2019). 31207605
  16. [22]Scott, A. C. et al. TOX is a critical regulator of tumour-specific T cell differentiation. Nature 571, 270–274 (2019). 31207604 PMC7698992
  17. [23]Yao, C. et al. Single-cell RNA-seq reveals TOX as a key regulator of CD8 + T cell persistence in chronic infection. Nat. Immunol. 20, 890–901 (2019). 31209400 PMC6588409
  18. [24]Crowl, J. T. et al. Tissue-resident memory CD8 + T cells possess unique transcriptional, epigenetic and functional adaptations to different tissue environments. Nat. Immunol. 23, 1121–1131 (2022). 35761084 PMC10041538
  19. [25]Kurd, N. S. et al. Early precursors and molecular determinants of tissue-resident memory CD8 + T lymphocytes revealed by single-cell RNA sequencing. Sci. Immunol. 5, eaaz6894 (2020). 32414833 PMC7341730
  20. [27]Chen, X. et al. The histone methyltransferase EZH2 primes the early differentiation of follicular helper T cells during acute viral infection. Cell. Mol. Immunol. 17, 247–260 (2020). 30842630 PMC7052164
  21. [28]Xu, L. et al. The transcription factor TCF-1 initiates the differentiation of T FH cells during acute viral infection. Nat. Immunol. 16, 991–999 (2015). 26214740
  22. [29]Crawford, A. et al. Molecular and transcriptional basis of CD4 + T cell dysfunction during chronic infection. Immunity 40, 289–302 (2014). 24530057 PMC3990591
  23. [30]Veldman, J. et al. CD4 + T cells in classical Hodgkin lymphoma express exhaustion associated transcription factors TOX and TOX2: characterizing CD4 + T cells in Hodgkin lymphoma. Oncoimmunology 11, 2033433 (2022). 35111387 PMC8803106
  24. [31]Beura, L. K. et al. CD4 + resident memory T cells dominate immunosurveillance and orchestrate local recall responses. J. Exp. Med. 216, 1214–1229 (2019). 30923043 PMC6504216
  25. [32]Milner, J. J. et al. Heterogenous populations of tissue-resident CD8 + T cells are generated in response to infection and malignancy. Immunity 52, 808–824 (2020). 32433949 PMC7784612
  26. [33]Vigil, A., Martinez, O., Chua, M. A. & García-Sastre, A. Recombinant Newcastle disease virus as a vaccine vector for cancer therapy. Mol. Ther. 16, 1883–1890 (2008). 18714310 PMC2878970
  27. [34]Zamarin, D. et al. Intratumoral modulation of the inducible co-stimulator ICOS by recombinant oncolytic virus promotes systemic anti-tumour immunity. Nat. Commun. 8, 14340 (2017). 28194010 PMC5316835
  28. [35]Fan, B. et al. Cholangiocarcinomas can originate from hepatocytes in mice. J. Clin. Invest. 122, 2911–2915 (2012). 22797301 PMC3408746
  29. [36]Behr, F. M. et al. Tissue-resident memory CD8 + T cells shape local and systemic secondary T cell responses. Nat. Immunol. 21, 1070–1081 (2020). 32661361
  30. [37]Boivin, W. A., Cooper, D. M., Hiebert, P. R. & Granville, D. J. Intracellular versus extracellular granzyme B in immunity and disease: challenging the dogma. Lab. Invest. 89, 1195–1220 (2009). 19770840 PMC7102238
  31. [38]Connolly, K. A. et al. A reservoir of stem-like CD8 + T cells in the tumor-draining lymph node preserves the ongoing antitumor immune response. Sci. Immunol. 6, eabg7836 (2021). 34597124 PMC8593910
  32. [39]Chiba, K. FTY720, a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1-phosphate receptors. Pharmacol. Ther. 108, 308–319 (2005). 15951022
  33. [40]Balança, C. C. et al. PD-1 blockade restores helper activity of tumor-infiltrating, exhausted PD-1 hi CD39 + CD4 T cells. JCI Insight 6, e142513 (2021). 33332284 PMC7934837
  34. [41]Conde, E. et al. Epitope spreading driven by the joint action of CART cells and pharmacological STING stimulation counteracts tumor escape via antigen-loss variants. J. Immunother. Cancer 9, e003351 (2021). 34810235 PMC8609946
  35. [42]Lai, J. et al. Adoptive cellular therapy with T cells expressing the dendritic cell growth factor Flt3L drives epitope spreading and antitumor immunity. Nat. Immunol. 21, 914–926 (2020). 32424363
  36. [43]Twumasi-Boateng, K., Pettigrew, J. L., Kwok, Y. Y. E., Bell, J. C. & Nelson, B. H. Oncolytic viruses as engineering platforms for combination immunotherapy. Nat. Rev. Cancer 18, 419–432 (2018). 29695749
  37. [44]Sette, A. & Crotty, S. Immunological memory to SARS-CoV-2 infection and COVID-19 vaccines. Immunol. Rev. 10, 27–46 (2022). PMC9349657 35733376
  38. [45]Yang, J. et al. A vaccine targeting the RBD of the S protein of SARS-CoV-2 induces protective immunity. Nature 586, 572–577 (2020). 32726802
  39. [46]Gao, L. et al. The dichotomous and incomplete adaptive immunity in COVID-19 patients with different disease severity. Signal Transduct. Target. Ther. 6, 113 (2021). 33686064 PMC7938043
  40. [48]Hasegawa, T. et al. Cytotoxic CD4 + T cells eliminate senescent cells by targeting cytomegalovirus antigen. Cell 186, 1417–1431 (2023). 37001502
  41. [49]Shin, D. H., Gillard, A., Van Wieren, A., Gomez-Manzano, C. & Fueyo, J. Remission of liquid tumors and SARS-CoV-2 infection: a literature review. Mol. Ther. Oncolytics 26, 135–140 (2022). 35702422 PMC9186532
  42. [50]Ottaiano, A. et al. Unexpected tumor reduction in metastatic colorectal cancer patients during SARS-Cov-2 infection. Ther. Adv. Med. Oncol. 13, 17588359211011455 (2021). 33995596 PMC8107669
  43. [51]Xia, P. & Dubrovska, A. Tumor markers as an entry for SARS-CoV-2 infection? FEBS J. 287, 3677–3680 (2020). 32738184 PMC7436716
  44. [52]Zhang, S. et al. Mediator complex subunit 12 is a gatekeeper of SARS-CoV-2 infection in breast cancer cells. Genes Dis. 9, 5–8 (2022). 34423104 PMC8372481
  45. [53]He, R. et al. Follicular CXCR5-expressing CD8 + T cells curtail chronic viral infection. Nature 537, 412–428 (2016). 27501245
  46. [54]Yu, X. H. et al. Roles of the polymerase-associated protein genes in Newcastle disease virus virulence. Front. Microbiol. 8, 161 (2017). 28220114 PMC5292418
  47. [55]Fallet, B. et al. Chronic viral infection promotes efficient germinal center B cell responses. Cell Rep. 30, 1013–1026 (2020). 31995746 PMC6996002
  48. [56]Butler, A., Hoffman, P., Smibert, P., Papalexi, E. & Satija, R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol. 36, 411–420 (2018). 29608179 PMC6700744
  49. [57]Germain, P. L., Lun, A., Garcia Meixide, C., Macnair, W. & Robinson, M. D. Doublet identification in single-cell sequencing data using scDblFinder. F1000Res. 10, 979 (2021). 35814628 PMC9204188
  50. [58]Kotliar, D. et al. Identifying gene expression programs of cell-type identity and cellular activity with single-cell RNA-seq. eLife 8, e43803 (2019). 31282856 PMC6639075
  51. [59]La Manno, G. et al. RNA velocity of single cells. Nature 560, 494–498 (2018). 30089906 PMC6130801
  52. [61]Beausang, J. F. et al. T cell receptor sequencing of early-stage breast cancer tumors identifies altered clonal structure of the T cell repertoire. Proc. Natl Acad. Sci. USA 114, E10409–E10417 (2017). 29138313 PMC5715779
  53. [62]Jia, Q. et al. Local mutational diversity drives intratumoral immune heterogeneity in non-small cell lung cancer. Nat. Commun. 9, 5361 (2018). 30560866 PMC6299138
  54. [63]Borcherding, N., Bormann, N. L. & Kraus, G. scRepertoire: an R-based toolkit for single-cell immune receptor analysis. F1000Res. 9, 47 (2020). 32789006 PMC7400693
  55. [64]Ye, L., Zeng, R., Bai, Y., Roopenian, D. C. & Zhu, X. Efficient mucosal vaccination mediated by the neonatal Fc receptor. Nat. Biotechnol. 29, 158–163 (2011). 21240266 PMC3197702

Authors
Chen, X., Zhao, J., Yue, S., Li, Z., Duan, X., Lin, Y., Yang, Y., He, J., Gao, L., Pan, Z., Yang, X., Su, X., Huang, M., Li, X., Zhao, Y., Zhang, X., Li, Z., Hu, L., Tang, J., Hao, Y., Tian, Q., Wang, Y., Xu, L., Huang, Q., Cao, Y., Chen, Y., Zhu, B., Li, Y., Bai, F., Zhang, G., & Ye, L.
Affiliations
  • Changping Laboratory (CN)
  • China Agricultural University (CN)
  • Army Medical University (CN)
  • Model Animal Research Center (CN)
  • Southern Medical University (CN)
  • Chongqing Medical University (CN)
  • Chongqing Public Health Medical Center (CN)
  • Peking University (CN)
Corresponding author
  • Li, Yan
  • Bai, Fan
  • Zhang, Guozhong
  • Ye, Lilin
ORCID
Venue
Nature Cancer
Publisher
Springer Science and Business Media LLC
Published
2024-04-12
Volume
5
Issue
7
Pages
1063-1081
ISSN
2662-1347 (ISSN-L)
DOI
10.1038/s43018-024-00760-x
PMC
PMC11286533
OpenAlex
W4394752969
Cited by
68
References
64
Citations by year
2026: 25 · 2025: 37 · 2024: 6
FWCI
11.37
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Cancer (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Greater South Information System
Funders
National Natural Science Foundation of China (32070942, 32300785)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
oncolytic viruses, bystander T cells, epitope spreading, tumor-specific T cells, tumor microenvironment, T cell exhaustion, cancer immunotherapy, SARS-CoV-2-specific T cells, COVID-19 vaccination, tumor xenografts
MeSH terms
COVID-19, SARS-CoV-2, Animals, Antigens, Neoplasm, Female, Humans, Immunotherapy, Neoplasms, T-Lymphocytes, Epitopes, T-Lymphocyte, Xenograft Model Antitumor Assays, Cell Line, Tumor, Oncolytic Virotherapy, Oncolytic Viruses, Mice, Tumor Microenvironment

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