存在于肿瘤内的具有细胞毒性潜力的预先存在的T细胞与头颈癌中新辅助抗PD-1治疗的疗效相关。
Preexisting tumor-resident T cells with cytotoxic potential associate with response to neoadjuvant anti-PD-1 in head and neck cancer.
发表日期：2023 Sep 08
作者：
Giacomo Oliveira, Ann Marie Egloff, Alexander B Afeyan, Jacquelyn O Wolff, Zexiang Zeng, Rebecca D Chernock, Liye Zhou, Cameron Messier, Patrick Lizotte, Kathleen L Pfaff, Kari Stromhaug, Livius Penter, Robert I Haddad, Glenn J Hanna, Jonathan D Schoenfeld, Laura A Goguen, Donald J Annino, Vickie Jo, Peter Oppelt, Patrik Pipkorn, Ryan Jackson, Sidharth V Puram, Randal C Paniello, Jason T Rich, Jason Webb, Jose P Zevallos, Mena Mansour, Jingxin Fu, Gavin P Dunn, Scott J Rodig, Jessica Ley, Luc G T Morris, Lara Dunn, Cloud P Paweletz, Dorina Kallogjeri, Jay F Piccirillo, Douglas R Adkins, Catherine J Wu, Ravindra Uppaluri
来源：
Cell Death & Disease
摘要：
约50%的局部晚期头颈鳞状细胞癌（HNSCC）患者在明确治疗后出现复发。术前给予抗 programmed cell death protein 1（PD-1）免疫治疗可使肿瘤微环境（TME）内发生显著的病理性肿瘤反应（pTR）。然而，术前 PD-1 阻滞对抗肿瘤 T 细胞动态的机制尚未解决，缺乏提高病理性反应的方法。根据一个第二期试验（NCT02296684）的观察，接受两剂术前帕博利珠单抗治疗的患者中有45%出现明显的pTR（≥50%）。对14个肿瘤活检标本中的17,158个 CD8+ T 细胞进行单细胞分析，其中包括6个术前-术后新辅助治疗标本，发现反应性肿瘤具有克隆扩张的疑似肿瘤特异性疲劳CD8+肿瘤浸润淋巴细胞（TILs），且具有高细胞毒潜能（CTX+）和 ZNF683 表达，属于组织驻留记忆程序。经过5周的 PD-1 阻滞后的病理学反应与之前存在的 CTX+ZNF683+CD8+ TILs 的激活一致，伴随着存活肿瘤和相关肿瘤抗原的丧失。反应与浸润术前病变的高数量 CD103+PD-1+CD8+ T 细胞相关，而非疲劳的持续存在的克隆和克隆置换相对较小。相反，不反应的术前 TME 缺乏 ZNF683+CTX+ TILs，且后来积累高度耗竭的克隆。在 HNSCC 中，复苏之前存在的 ZNF683+CTX+ TILs 是术后新辅助设置中的主要响应机制。
About 50% of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) experience recurrences after definitive therapy. The presurgical administration of anti-programmed cell death protein 1 (PD-1) immunotherapy results in substantial pathologic tumor responses (pTR) within the tumor microenvironment (TME). However, the mechanisms underlying the dynamics of antitumor T cells upon neoadjuvant PD-1 blockade remain unresolved, and approaches to increase pathologic responses are lacking. In a phase 2 trial (NCT02296684), we observed that 45% of patients treated with two doses of neoadjuvant pembrolizumab experienced marked pTRs (≥50%). Single-cell analysis of 17,158 CD8+ T cells from 14 tumor biopsies, including 6 matched pre-post neoadjuvant treatment, revealed that responding tumors had clonally expanded putative tumor-specific exhausted CD8+ tumor-infiltrating lymphocytes (TILs) with a tissue-resident memory program, characterized by high cytotoxic potential (CTX+) and ZNF683 expression, within the baseline TME. Pathologic responses after 5 weeks of PD-1 blockade were consistent with activation of preexisting CTX+ZNF683+CD8+ TILs, paralleling loss of viable tumor and associated tumor antigens. Response was associated with high numbers of CD103+PD-1+CD8+ T cells infiltrating pretreatment lesions, whereas revival of nonexhausted persisting clones and clonal replacement were modest. By contrast, nonresponder baseline TME exhibited a relative absence of ZNF683+CTX+ TILs and subsequent accumulation of highly exhausted clones. In HNSCC, revival of preexisting ZNF683+CTX+ TILs is a major mechanism of response in the immediate postneoadjuvant setting.