阴茎鳞状细胞癌中的免疫疗法：现状还是未来？程序性细胞死亡配体1表达与微卫星不稳定性的多靶点分析

Immunotherapy in Penile Squamous Cell Carcinoma: Present or Future? Multi-Target Analysis of Programmed Cell Death Ligand 1 Expression and Microsatellite Instability.

作者信息

Montella Marco, Sabetta Rosalaura, Ronchi Andrea, De Sio Marco, Arcaniolo Davide, De Vita Ferdinando, Tirino Giuseppe, Caputo Alessandro, D'Antonio Antonio, Fiorentino Francesco, Facchini Gaetano, Lauro Giovanni Di, Perdonà Sisto, Ventriglia Jole, Aquino Gabriella, Feroce Florinda, Borges Dos Reis Rodolfo, Neder Luciano, Brunelli Matteo, Franco Renato, Zito Marino Federica

机构信息

Pathology Unit, Department of Mental Health, Physic and Preventive Medicine University of Campania "Luigi Vanvitelli", Naples, Italy.

Urology Unit, Department of Woman Child and of General and Specialist Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy.

出版信息

Front Med (Lausanne). 2022 May 3;9:874213. doi: 10.3389/fmed.2022.874213. eCollection 2022.

BACKGROUND

Penile cancer (PC) is an extremely rare malignancy, and the patients at advanced stages have currently limited treatment options with disappointing results. Immune checkpoint inhibitors anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) are currently changing the treatment of several tumors. Furthermore, the microsatellite instability (MSI) and the deficient mismatch repair system (dMMR) proteins represent predictive biomarkers for response to immune checkpoint therapy. Until present, few data have been reported related to PD-L1 expression and MSI in PC. The main aim of our study was the evaluation of PD-L1 expression in tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs) in immune cells and the analysis of dMMR/MSI status in a large series of PCs.

METHODS

A series of 72 PC, including 65 usual squamous cell carcinoma (USCC), 1 verrucous, 4 basaloid, 1 warty, and 1 mixed (warty-basaloid), was collected. Immunohistochemistry (IHC) was performed to assess PD-L1 expression using two different anti-PD-L1 antibodies (clone SP263 and SP142 Ventana) and MMR proteins expression using anti-MLH1, anti-PMS2, anti-MSH2, and anti-MSH6 antibodies. PCR analysis was performed for the detection of MSI status.

RESULTS

Of the 72 PC cases analyzed by IHC, 45 (62.5%) cases were TC positive and 57 (79%) cases were combined positive score (CPS) using PDL1 SP263. In our cohort, TILs were present in 62 out of 72 cases (86.1%), 47 (75.8%) out of 62 cases showed positivity to PDL1 clone SP142. In our series, 59 cases (82%) had pMMR, 12 cases (16.7%) had lo-paMMR, and only 1 case (1.3%) had MMR. PCR results showed that only one case lo-paMMR was MSI-H, and the case dMMR by IHC not confirmed MSI status.

CONCLUSION

Our findings showed that PD-L1 expression and MSI status represent frequent biological events in this tumor suggesting a rationale for a new frontier in the treatment of patients with PC based on the immune checkpoint inhibitors.

背景

阴茎癌（PC）是一种极为罕见的恶性肿瘤，晚期患者目前的治疗选择有限，效果令人失望。免疫检查点抑制剂抗程序性细胞死亡蛋白1（PD-1）/程序性细胞死亡配体1（PD-L1）目前正在改变多种肿瘤的治疗方式。此外，微卫星不稳定性（MSI）和错配修复缺陷系统（dMMR）蛋白是免疫检查点治疗反应的预测生物标志物。到目前为止，关于阴茎癌中PD-L1表达和MSI的报道数据很少。我们研究的主要目的是评估肿瘤细胞（TCs）和免疫细胞中肿瘤浸润淋巴细胞（TILs）的PD-L1表达，并分析大量阴茎癌病例的dMMR/MSI状态。

方法

收集了一系列72例阴茎癌病例，包括65例常见鳞状细胞癌（USCC）、1例疣状癌、4例基底样癌、1例疣状癌和1例混合性（疣状-基底样）癌。采用两种不同的抗PD-L1抗体（克隆号SP263和SP142 Ventana）进行免疫组织化学（IHC）检测以评估PD-L1表达，使用抗MLH1、抗PMS2、抗MSH2和抗MSH6抗体检测MMR蛋白表达。进行PCR分析以检测MSI状态。

结果

在通过IHC分析的72例阴茎癌病例中，45例（62.5%）病例的肿瘤细胞呈阳性，使用PDL1 SP263时57例（79%）病例的综合阳性评分（CPS）为阳性。在我们的队列中，72例病例中有62例（86.1%）存在肿瘤浸润淋巴细胞，62例中的47例（75.8%）对PDL1克隆号SP142呈阳性。在我们的系列病例中，59例（82%）为错配修复功能完整（pMMR），12例（16.7%）为低水平错配修复功能部分缺失（lo-paMMR），只有1例（1.3%）为错配修复缺陷（dMMR）。PCR结果显示，只有1例lo-paMMR病例为微卫星高度不稳定（MSI-H），而通过IHC检测为dMMR的病例未得到MSI状态的证实。