An EBV-related CD4 TCR immunotherapy inhibits tumor growth in an HLA-DP5+ nasopharyngeal cancer mouse model
Adoptive transfer of T cell receptor-engineered T cells (TCR-T) is a promising strategy for immunotherapy against solid tumors. However, the potential of CD4+ T cells in mediating tumor regression has been neglected. Nasopharyngeal cancer is consistently associated with EBV. Here, to evaluate the therapeutic potential of CD4 TCR-T in nasopharyngeal cancer, we screened for CD4 TCRs recognizing EBV nuclear antigen 1 (EBNA1) presented by HLA-DP5. Using mass spectrometry, we identified EBNA1567-581, a peptide naturally processed and presented by HLA-DP5. We isolated TCR135, a CD4 TCR with high functional avidity, that can function in both CD4+ and CD8+ T cells and recognizes HLA-DP5-restricted EBNA1567-581. TCR135-transduced T cells functioned in two ways: directly killing HLA-DP5+EBNA1+ tumor cells after recognizing EBNA1 presented by tumor cells and indirectly killing HLA-DP5-negative tumor cells after recognizing EBNA1 presented by antigen-presenting cells. TCR135-transduced T cells preferentially infiltrated into the tumor microenvironment and significantly inhibited tumor growth in xenograft nasopharyngeal tumor models. Additionally, we found that 62% of nasopharyngeal cancer patients showed 50%-100% expression of HLA-DP on tumor cells, indicating that nasopharyngeal cancer is well suited for CD4 TCR-T therapy. These findings suggest that TCR135 may provide a new strategy for EBV-related nasopharyngeal cancer immunotherapy in HLA-DP5+ patients.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:134 |
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| Enthalten in: |
The Journal of clinical investigation - 134(2024), 8 vom: 27. Feb. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wang, Chenwei [VerfasserIn] |
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| Links: |
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| Themen: |
Cancer immunotherapy |
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| Anmerkungen: |
Date Completed 16.04.2024 Date Revised 16.04.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1172/JCI172092 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM369019903 |
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| 245 | 1 | 3 | |a An EBV-related CD4 TCR immunotherapy inhibits tumor growth in an HLA-DP5+ nasopharyngeal cancer mouse model |
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| 520 | |a Adoptive transfer of T cell receptor-engineered T cells (TCR-T) is a promising strategy for immunotherapy against solid tumors. However, the potential of CD4+ T cells in mediating tumor regression has been neglected. Nasopharyngeal cancer is consistently associated with EBV. Here, to evaluate the therapeutic potential of CD4 TCR-T in nasopharyngeal cancer, we screened for CD4 TCRs recognizing EBV nuclear antigen 1 (EBNA1) presented by HLA-DP5. Using mass spectrometry, we identified EBNA1567-581, a peptide naturally processed and presented by HLA-DP5. We isolated TCR135, a CD4 TCR with high functional avidity, that can function in both CD4+ and CD8+ T cells and recognizes HLA-DP5-restricted EBNA1567-581. TCR135-transduced T cells functioned in two ways: directly killing HLA-DP5+EBNA1+ tumor cells after recognizing EBNA1 presented by tumor cells and indirectly killing HLA-DP5-negative tumor cells after recognizing EBNA1 presented by antigen-presenting cells. TCR135-transduced T cells preferentially infiltrated into the tumor microenvironment and significantly inhibited tumor growth in xenograft nasopharyngeal tumor models. Additionally, we found that 62% of nasopharyngeal cancer patients showed 50%-100% expression of HLA-DP on tumor cells, indicating that nasopharyngeal cancer is well suited for CD4 TCR-T therapy. These findings suggest that TCR135 may provide a new strategy for EBV-related nasopharyngeal cancer immunotherapy in HLA-DP5+ patients | ||
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| 700 | 1 | |a Xu, Zhihong |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Lihong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Qian |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Lei |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Xiaolong |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Hai |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Gang |e verfasserin |4 aut | |
| 700 | 1 | |a Xiong, Chengjie |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Bin |e verfasserin |4 aut | |
| 700 | 1 | |a You, Hua |e verfasserin |4 aut | |
| 700 | 1 | |a Du, Danyi |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xiaoling |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Hongle |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Zibing |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Lin |e verfasserin |4 aut | |
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