尽管免疫检查点抑制剂 (CPI) 彻底改变了默克尔细胞癌 (MCC) 的治疗，但 CPI 难治性 MCC 患者缺乏有效的治疗方法。超过 80% 的 MCC 表达默克尔细胞多瘤病毒编码的 T 抗原，这是基于 T 细胞受体 (TCR) 的免疫治疗的理想靶标。然而，MCC 经常抑制 HLA 表达，需要额外的策略来逆转下调，从而使 T 细胞能够识别其目标。我们鉴定出 TCR MCC1 可以识别仅限于人类白细胞抗原 (HLA)-A*02:01 的 T 抗原表位。 7 名 CPI 难治性转移性 MCC 患者接受了 TCR MCC1 (T TCR-MCC1 ) 转导的 CD4 和 CD8 T 细胞，然后进行淋巴细胞清除化疗或 HLA 上调方案（单次放射治疗 (SFRT) 或全身干扰素 γ (IFNγ)） ）与同时的 avelumab。先前接受 SFRT 和 IFNγ 治疗的两名患者分别经历了肿瘤消退。一个患者的 13/14 个皮下病变消退，其中 1 个“逃逸”病变，另一个患者在初始进展后所有病变的肿瘤消退均延迟。尽管具有激活表型的 T TCR-MCC1 细胞浸润了包括“逃逸”病变在内的肿瘤，但所有进展性病变在转录上均缺乏 HLA 表达。虽然 SFRT/IFNγ 并未立即上调肿瘤 HLA 表达，但在其中一个消退的肿瘤中检测到二次内源性抗原特异性 T 细胞浸润，并且与 HLA 上调相关，表明原位免疫反应有可能逆转 HLA 下调。事实上，在异种移植小鼠模型中，通过 CD200R-CD28 开关受体提供强烈的共刺激信号，T TCR-MCC1 细胞可以控制 HLA 下调的 MCC 细胞，从而上调 HLA 表达。我们的结果证明了 TCR 基因治疗治疗转移性 MCC 的潜力，并提出了克服 MCC 中 HLA 表观遗传下调的下一个策略。

Although immune check-point inhibitors (CPIs) revolutionized treatment of Merkel cell carcinoma (MCC), patients with CPI-refractory MCC lack effective therapy. More than 80% of MCC express T-antigens encoded by Merkel cell polyomavirus, which is an ideal target for T-cell receptor (TCR)-based immunotherapy. However, MCC often repress HLA expression, requiring additional strategies to reverse the downregulation for allowing T cells to recognize their targets. We identified TCR MCC1 that recognizes a T-antigen epitope restricted to human leukocyte antigen (HLA)-A*02:01. Seven CPI-refractory metastatic MCC patients received CD4 and CD8 T cells transduced with TCR MCC1 (T TCR-MCC1 ) preceded either by lymphodepleting chemotherapy or an HLA-upregulating regimen (single-fraction radiation therapy (SFRT) or systemic interferon gamma (IFNγ)) with concurrent avelumab. Two patients who received preceding SFRT and IFNγ respectively experienced tumor regression. One experienced regression of 13/14 subcutaneous lesions with 1 'escape' lesion and the other had delayed tumor regression in all lesions after initial progression. Although T TCR-MCC1 cells with an activated phenotype infiltrated tumors including the 'escape' lesion, all progressing lesions transcriptionally lacked HLA expression. While SFRT/IFNγ did not immediately upregulate tumor HLA expression, a secondary endogenous antigen-specific T cell infiltrate was detected in one of the regressing tumors and associated with HLA upregulation, indicating in situ immune responses have the potential to reverse HLA downregulation. Indeed, supplying a strong co-stimulatory signal via a CD200R-CD28 switch receptor allows T TCR-MCC1 cells to control HLA-downregulated MCC cells in a xenograft mouse model, upregulating HLA expression. Our results demonstrate the potential of TCR gene therapy for metastatic MCC and propose a next strategy for overcoming epigenetic downregulation of HLA in MCC.