An EBV-related CD4 TCR immunotherapy inhibits tumor growth in an [HLA-DP5.sup.+] nasopharyngeal cancer mouse model

• Published in: The Journal of clinical investigation 2024-04, Vol.134 (8)
• Main Authors: Wang, Chenwei, Chen, Jiewen, Li, Jingyao, Xu, Zhihong, Huang, Lihong, Zhao, Qian, Chen, Lei, Liang, Xiaolong, Hu, Hai, Li, Gang, Xiong, Chengjie, Wu, Bin, You, Hua, Du, Danyi, Wang, Xiaoling, Li, Hongle, Wang, Zibing, Chen, Lin
• Format: Article
• Language: English
• Subjects: Analysis; Antigens; Cancer; Care and treatment; Diagnosis; Dosage and administration; Drug therapy; Growth; Health aspects; Immunotherapy; Mass spectrometry; Nasopharyngeal cancer; Patient outcomes; Peptides; T cells; Testing
• ISSN: 0021-9738
• DOI: 10.1172/JCI172092

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.sup.+] 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 [EBNA1.sub.567-581], 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.sup.+] and [CD8.sup.+] T cells and recognizes HLA-DP5-restricted [EBNA1.sub.567-581]. TCR135-transduced T cells functioned in two ways: directly killing [HLA-DP5.sup.+][EBNA1.sup.+] 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.sup.+] patients.