An EBV-related CD4 TCR immunotherapy inhibits tumor growth in an HLA-DP5+ nasopharyngeal cancer mouse model
Chenwei Wang, Jiewen Chen, Jingyao Li, Zhihong Xu, Lihong Huang, Qian Zhao, Lei Chen, Xiaolong Liang, Hai Hu, Gang Li, Chengjie Xiong, Bin Wu, Hua You, Danyi Du, Xiaoling Wang, Hongle Li, Zibing Wang, Lin Chen
Chenwei Wang, Jiewen Chen, Jingyao Li, Zhihong Xu, Lihong Huang, Qian Zhao, Lei Chen, Xiaolong Liang, Hai Hu, Gang Li, Chengjie Xiong, Bin Wu, Hua You, Danyi Du, Xiaoling Wang, Hongle Li, Zibing Wang, Lin Chen
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Research Article Immunology

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

Abstract

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.

Authors

Chenwei Wang, Jiewen Chen, Jingyao Li, Zhihong Xu, Lihong Huang, Qian Zhao, Lei Chen, Xiaolong Liang, Hai Hu, Gang Li, Chengjie Xiong, Bin Wu, Hua You, Danyi Du, Xiaoling Wang, Hongle Li, Zibing Wang, Lin Chen

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Figure 8

HLA-DP and EBNA1 expression on NPC and gastric cancer cells.

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HLA-DP and EBNA1 expression on NPC and gastric cancer cells. (A and B) T...
(A and B) The tumor tissue microarray of NPC (n = 112) was stained with anti–HLA-DPB1 antibody by immunohistochemistry and was scored by the proportion of HLA-DP+ tumor cells in total tumor cells (A). The quantitative result is shown in the pie chart (B). Scale bars: 100 μm. (C and D) The tumor tissue microarray of gastric cancer (n = 75) was stained with anti–HLA-DPB1 antibody by immunohistochemistry and was scored by the proportion of HLA-DP+ tumor cells in total tumor cells (C). The quantitative result is shown in the pie chart (D). Scale bars: 100 μm. (E) The tumor tissue sections of C666-1 or C666-1-EBNA1 mouse xenograft and the tumor tissue microarray of NPC patients were stained using an anti-EBNA1 antibody. The staining intensity of EBNA1 in the tumor tissue microarray of NPC patients was scored, and the quantitative results (n = 107) are shown in the pie chart. Scale bars: 100 μm. (F) TCR135-transduced T cells (TCR135-T) or non-transduced T cells (TCRneg-T) were cocultured with PDOs for 48 hours, and then bright-field images were captured. The representative microscopy images are shown. Scale bars: 50 μm.