美国加州大学洛杉矶分校Antoni Ribas等研究人员合作发现，新抗原靶向的CD8⁺T细胞响应PD-1阻断疗法。相关论文于2023年3月8日在线发表于国际学术期刊《自然》。

研究人员表示，新抗原是由人类白细胞抗原（HLA）呈现的非同义突变所衍生的肽，可被抗肿瘤T细胞识别。巨大的HLA等位基因多样性和有限的临床样本限制了对患者治疗过程中新抗原靶向T细胞反应的研究。研究人员应用最近开发的技术，从对抗程序化死亡受体1（PD-1）免疫疗法有或无反应的转移性黑色素瘤患者的血液和肿瘤中捕捉新抗原特异性T细胞。

研究人员产生了个性化的新抗原-HLA捕获试剂库，以单细胞分离T细胞并克隆其T细胞受体（neoTCR）。具有不同neoTCR序列的多个T细胞（T细胞克隆型）在7名具有长期临床反应的患者的样本中识别了数量有限的突变。这些新TCR克隆型随着时间的推移在血液和肿瘤中反复检测。来自四名对抗PD-1没有反应的患者的样本也显示了血液和肿瘤中对数量有限的突变的新抗原特异性T细胞反应，其TCR多克隆性较低，并且在连续的样本中没有重复检测到。使用非病毒CRISPR-Cas9基因编辑在供体T细胞中重组新TCR，研究人员证明了对患者匹配的黑色素瘤细胞系的特异性识别和细胞毒性。因此，有效的抗PD-1免疫疗法与肿瘤和血液中存在的多克隆CD8⁺T细胞有关，这些细胞对有限数量的免疫显性突变具有特异性，并随着时间的推移反复识别。

附：英文原文

Title: Neoantigen-targeted CD8+ T cell responses with PD-1 blockade therapy

Author: Puig-Saus, Cristina, Sennino, Barbara, Peng, Songming, Wang, Clifford L., Pan, Zheng, Yuen, Benjamin, Purandare, Bhamini, An, Duo, Quach, Boi B., Nguyen, Diana, Xia, Huiming, Jilani, Sameeha, Shao, Kevin, McHugh, Claire, Greer, John, Peabody, Phillip, Nayak, Saparya, Hoover, Jonathan, Said, Sara, Jacoby, Kyle, Dalmas, Olivier, Foy, Susan P., Conroy, Andrew, Yi, Michael C., Shieh, Christine, Lu, William, Heeringa, Katharine, Ma, Yan, Chizari, Shahab, Pilling, Melissa J., Ting, Marc, Tunuguntla, Ramya, Sandoval, Salemiz, Moot, Robert, Hunter, Theresa, Zhao, Sidi, Saco, Justin D., Perez-Garcilazo, Ivan, Medina, Egmidio, Vega-Crespo, Agustin, Baselga-Carretero, Ignacio, Abril-Rodriguez, Gabriel, Cherry, Grace, Wong, Deborah J., Hundal, Jasreet, Chmielowski, Bartosz, Speiser, Daniel E., Bethune, Michael T., Bao, Xiaoyan R., Gros, Alena, Griffith, Obi L., Griffith, Malachi, Heath, James R., Franzusoff, Alex, Mandl, Stefanie J., Ribas, Antoni

Issue&Volume: 2023-03-08

Abstract: Neoantigens are peptides derived from non-synonymous mutations presented by human leukocyte antigens (HLAs), which are recognized by antitumour T cells1,2,3,4,5,6,7,8,9,10,11,12,13,14. The large HLA allele diversity and limiting clinical samples have restricted the study of the landscape of neoantigen-targeted T cell responses in patients over their treatment course. Here we applied recently developed technologies15,16,17 to capture neoantigen-specific T cells from blood and tumours from patients with metastatic melanoma with or without response to anti-programmed death receptor 1 (PD-1) immunotherapy. We generated personalized libraries of neoantigen–HLA capture reagents to single-cell isolate the T cells and clone their T cell receptors (neoTCRs). Multiple T cells with different neoTCR sequences (T cell clonotypes) recognized a limited number of mutations in samples from seven patients with long-lasting clinical responses. These neoTCR clonotypes were recurrently detected over time in the blood and tumour. Samples from four patients with no response to anti-PD-1 also demonstrated neoantigen-specific T cell responses in the blood and tumour to a restricted number of mutations with lower TCR polyclonality and were not recurrently detected in sequential samples. Reconstitution of the neoTCRs in donor T cells using non-viral CRISPR–Cas9 gene editing demonstrated specific recognition and cytotoxicity to patient-matched melanoma cell lines. Thus, effective anti-PD-1 immunotherapy is associated with the presence of polyclonal CD8+ T cells in the tumour and blood specific for a limited number of immunodominant mutations, which are recurrently recognized over time.

DOI: 10.1038/s41586-023-05787-1

Source: https://www.nature.com/articles/s41586-023-05787-1