T cell receptor–engineered T cells targeting the TP53R248Q neoantigen elicit antitumor effects in human cancer models
Lianghua Shen, Ziyu Chen, Jian Xu, Qiaomei He, Changmeng Zhang, Xiao Zhou, Xiaodan Ding, Jinan Fang, Fanlin Li, Ming Jiao, Yuqin Yang, Baoxia Dong, Liping Wan, Xueying Ding, Yan Zheng, Jingyi Zhou, Chijian Zuo, Tian Min, Ming Zhu, Bin Ma, Yuhua Wan, Qiufang Guo, Hua Zhang, Jian Hua, Pengran Wang, Qi Li, Jiang Long, Xianmin Song, Yan Zhang
Lianghua Shen, Ziyu Chen, Jian Xu, Qiaomei He, Changmeng Zhang, Xiao Zhou, Xiaodan Ding, Jinan Fang, Fanlin Li, Ming Jiao, Yuqin Yang, Baoxia Dong, Liping Wan, Xueying Ding, Yan Zheng, Jingyi Zhou, Chijian Zuo, Tian Min, Ming Zhu, Bin Ma, Yuhua Wan, Qiufang Guo, Hua Zhang, Jian Hua, Pengran Wang, Qi Li, Jiang Long, Xianmin Song, Yan Zhang
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Research Article Immunology Oncology

T cell receptor–engineered T cells targeting the TP53R248Q neoantigen elicit antitumor effects in human cancer models

Abstract

Malignant tumors with TP53 mutations exhibit poor therapeutic outcomes and high recurrence rates. T cell receptor–based (TCR-based) T cell therapy shows great promise for targeting intracellular cancer neoantigens. However, the immunogenic potential of TP53 hotspot mutations remains poorly characterized. Here, we identified an immunogenic neoantigen derived from the recurrent TP53R248Q mutation, presented by the prevalent HLA-A*11:01 allele. Additionally, we isolated a TP53R248Q-reactive TCR that specifically recognized the TP53R248Q mutation without any discernible cross-activity with cognate WT TP53 or other TP53 mutants at the same codon position. Functional characterization revealed that TP53R248Q TCR-T cells exhibited selective cytotoxicity against tumor cells expressing both the TP53R248Q mutation and HLA-A*11:01 in vitro. Importantly, the adoptive transfer of TP53R248Q TCR-T cells exhibited significant antitumor activity in a clinically relevant patient-derived xenograft model engrafted with TP53R248Q/HLA-A*11:01–positive human tumor tissues. Collectively, our study validates the immunogenicity of the TP53R248Q hotspot mutation and provides a TCR with high therapeutic potential for the development of T cell therapies targeting TP53R248Q/HLA-A*11:01–positive cancers.

Authors

Lianghua Shen, Ziyu Chen, Jian Xu, Qiaomei He, Changmeng Zhang, Xiao Zhou, Xiaodan Ding, Jinan Fang, Fanlin Li, Ming Jiao, Yuqin Yang, Baoxia Dong, Liping Wan, Xueying Ding, Yan Zheng, Jingyi Zhou, Chijian Zuo, Tian Min, Ming Zhu, Bin Ma, Yuhua Wan, Qiufang Guo, Hua Zhang, Jian Hua, Pengran Wang, Qi Li, Jiang Long, Xianmin Song, Yan Zhang

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Figure 4

TP53R248Q TCR-T cells recognize TP53R248Q neopeptide/HLA-A*11:01 complex with high specificity and low cross-reactivity profile.

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TP53R248Q TCR-T cells recognize TP53R248Q neopeptide/HLA-A*11:01 complex...
(A) Schematic representation of the 9-peptide sequence used in the “A” substitution experiments. (B and C) K562A11 cells were loaded with (5 μg/mL) TP53R248WT, TP53R248Q, and TP53R248Q neopeptides with different “A” substitution sites and then cocultured for 24 hours with TCR-T cells. Subsequently, flow cytometry was performed to detect the expression levels of CD137 and CD69 in TCR-T cells. (D) Schematic representation of the 9-peptide sequence used in the “G” substitution experiments. (E and F) K562A11 cells were loaded with (5 μg/mL) TP53R248WT, TP53R248Q, and TP53R248Q neopeptides with different “G” substitution sites, and then the expression levels of CD137 and CD69 in TCR-T cells was detected. (G) Peptides for which the “xxMGGxxQR” motif is present in the human proteome database, and their protein names were retrieved using PROSITE. (H) Nine predicted peptides were loaded onto K562A11 cells, and then the expression levels of CD137 in TCR-T cells were detected. (I) Representative SPR sensorgram measuring the dissociation constant (KD) for TP53R248Q TCR to the pR248Q/HLA-A*11:01 complex. The curves show kinetic fits (concentration: 250–8,000 nM). (J) Structural overview of the TP53R248Q TCR-pR248Q/HLA-A*11:01 or TP53R248Q TCR-pR248WT/HLA-A*11:01 ternary complex. (K) Schematic representation of the 9-peptide sequence used in the “Q” mutation scanning experiments. (L and M) K562A11 cells were loaded with (5 μg/mL) TP53R248WT or TP53R248Q neopeptides with different “Q” mutation sites, and then the expression levels of CD137 and CD69 in TCR-T cells (cocultured for 24 hours) was detected. Data are presented as the mean ± SEM; n = 3. In B, C, E, F, H, L, and M, 2-way ANOVA were used. The P values for B, C, E, and F were relative to the TP53R248Q neopeptide group, and the P values for H, L, and M were relative to the TP53R248WT peptide group.