Zhang Wanli, Shi Xupeiyao, Huang Shitong, Yu Qiumin, Wu Zijie, Xie Wenbin, Li Binghua, Xu Yanchao, Gao Zheng, Li Guozhi, Qian Qianqian, He Tiandi, Zheng Jiaxue, Zhang Tingran, Tong Yue, Deng Danni, Gao Xiangdong, Tian Hong, Yao Wenbing
Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, People's Republic of China.
Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, People's Republic of China.
Cancer Immunol Immunother. 2024 Oct 3;73(12):245. doi: 10.1007/s00262-024-03830-2.
Neoantigen vaccines represent an emerging and promising strategy in the field of tumor immunotherapy. Despite their potential, designing an effective neoantigen vaccine remains a challenge due to the current limitations in predicting CD4 T cell epitopes with high accuracy. Here, we introduce a novel approach to neoantigen vaccine design that does not rely on computational prediction of CD4 T cell epitopes. Utilizing nitrated helper T cell epitope containing p-nitrophenylalanine, termed "NitraTh epitope," we have successfully engineered a series of tumor neoantigen vaccines capable of eliciting robust neoantigen-specific immune responses. With the help of NitraTh epitope, even mutations with low predicted affinity for MHC class I molecules were successfully induced to elicit neoantigen-specific responses. In H22 cell allograft and patient-derived xenograft (PDX) liver cancer mouse models, the NitraTh epitope-based neoantigen vaccines significantly suppressed tumor progression. More strikingly, through single-cell sequencing we found that the NitraTh epitope-based neoantigen vaccines regulate macrophage reprogramming and modulate macrophages to decrease the levels of the immunosuppressive molecule prostaglandin E2 (PGE2), which in turn reshapes the tumor immunosuppressive microenvironment. In summary, NitraTh epitope-based neoantigen vaccines possess the dual effects of potently activating neoantigen-specific immunity and alleviating immunosuppression, potentially providing a new paradigm for the design of tumor neoantigen vaccines.
新抗原疫苗是肿瘤免疫治疗领域中一种新兴且有前景的策略。尽管具有潜力，但由于目前在高精度预测CD4 T细胞表位方面存在局限性，设计一种有效的新抗原疫苗仍然是一项挑战。在此，我们介绍一种新的新抗原疫苗设计方法，该方法不依赖于CD4 T细胞表位的计算预测。利用含有对硝基苯丙氨酸的硝化辅助性T细胞表位（称为“NitraTh表位”），我们成功构建了一系列能够引发强大的新抗原特异性免疫反应的肿瘤新抗原疫苗。借助NitraTh表位，即使是对MHC I类分子预测亲和力较低的突变也能成功诱导产生新抗原特异性反应。在H22细胞同种异体移植和患者来源的异种移植（PDX）肝癌小鼠模型中，基于NitraTh表位的新抗原疫苗显著抑制了肿瘤进展。更引人注目的是，通过单细胞测序我们发现，基于NitraTh表位的新抗原疫苗可调节巨噬细胞重编程并调节巨噬细胞，以降低免疫抑制分子前列腺素E2（PGE2）的水平，进而重塑肿瘤免疫抑制微环境。总之，基于NitraTh表位的新抗原疫苗具有有效激活新抗原特异性免疫和减轻免疫抑制的双重作用，可能为肿瘤新抗原疫苗的设计提供一种新的范例。
