Toberer Ferdinand, Winkler Julia K, Atienza Fernandez Leroy, Adams Lea, Brobeil Alexander, Tóth Marcell, Enk Alexander H, Becker Jürgen C, Lonsdorf Anke
Department of Dermatology, University Hospital Heidelberg, Heidelberg, Germany.
Departments of Translational Skin Cancer Research and Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Acta Derm Venereol. 2025 Jul 1;105:adv42882. doi: 10.2340/actadv.v105.42882.
Merkel cell carcinoma is a rare, aggressive skin cancer in which Merkel cell polyoma virus (MCPyV) is frequently pathogenically involved. After failure of anti-programmed cell death protein 1/programmed cell death ligand 1 immunotherapy, therapeutic options for advanced disease are limited. The contribution of the coinhibitory checkpoint molecule T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), a regulator of exhausted CD8+ T cells, to the immunosuppressive Merkel cell carcinoma microenvironment is understudied. This study evaluated the immunohistochemical expression of tumour (Tumor Proportion Score, TPS) and infiltrating immune cells (Immune Cell Score, ICS) for programmed cell death ligand 1, TIGIT, its high-affinity receptor CD155, and CD8 in 21 primary Merkel cell carcinoma and 6 metastases. Unlike CD155, TIGIT was abundantly expressed by tumour and immune cells and independent of the MCPyV status, determined by RT-PCR. Programmed cell death ligand 1+ immune cells were significantly increased in TIGIT TPS-positive and MCPyV-positive primary MCC along with significant intercorrelations of programmed cell death ligand 1 and TIGIT immune cell expression and CD8+ infiltrates. Programmed cell death ligand 1 IC-positivity correlated with superior disease-specific survival. The data indicate that TIGIT may contribute to local immune dysfunction in Merkel cell carcinoma, beyond programmed cell death ligand 1 and independent of MCPyV, and provide a rationale to further explore TIGIT as a potential target for Merkel cell carcinoma immunotherapy.
默克尔细胞癌是一种罕见的侵袭性皮肤癌，默克尔细胞多瘤病毒（MCPyV）常与之发病机制相关。抗程序性细胞死亡蛋白1/程序性细胞死亡配体1免疫疗法失败后，晚期疾病的治疗选择有限。共抑制性检查点分子T细胞免疫受体（具有免疫球蛋白和基于免疫受体酪氨酸的抑制基序结构域，即TIGIT）作为耗竭性CD8 + T细胞的调节因子，对免疫抑制性默克尔细胞癌微环境的作用尚未得到充分研究。本研究评估了21例原发性默克尔细胞癌和6例转移灶中程序性细胞死亡配体1、TIGIT、其高亲和力受体CD155和CD8在肿瘤（肿瘤比例评分，TPS）和浸润免疫细胞（免疫细胞评分，ICS）中的免疫组化表达。与CD155不同，TIGIT在肿瘤细胞和免疫细胞中大量表达，且与通过RT-PCR确定的MCPyV状态无关。在TIGIT TPS阳性和MCPyV阳性的原发性默克尔细胞癌中，程序性细胞死亡配体1 +免疫细胞显著增加，同时程序性细胞死亡配体1和TIGIT免疫细胞表达与CD8 +浸润之间存在显著的相互关系。程序性细胞死亡配体1 IC阳性与较好的疾病特异性生存率相关。数据表明，TIGIT可能导致默克尔细胞癌局部免疫功能障碍，这超出了程序性细胞死亡配体1的作用且与MCPyV无关，并为进一步探索TIGIT作为默克尔细胞癌免疫治疗的潜在靶点提供了理论依据。
