PD-L1 expression, tumor-infiltrating lymphocytes, mismatch repair deficiency, EGFR alteration and HPV infection in sinonasal squamous cell carcinoma
PD-L1 expression, tumor-infiltrating lymphocytes, mismatch repair deficiency, EGFR alteration and HPV infection in sinonasal squamous cell carcinoma
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DOI：
10.1038/s41379-021-00868-w
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发表时间：
2021-07-03
期刊：
影响因子：
7.5
通讯作者：
Oda, Yoshinao
中科院分区：
文献类型：
--
作者：
Hongo, Takahiro;Yamamoto, Hidetaka;Oda, Yoshinao
免疫检查点抑制剂（ICI）的抗肿瘤疗效和潜在预测标志物（如程序性死亡配体1（PD-L1）表达、肿瘤浸润淋巴细胞（TIL）密度和微卫星不稳定性（MSI））在鼻腔鼻窦鳞状细胞癌（SNSCC）中的作用尚未完全阐明。我们回顾性分析了131例SNSCC的PD-L1表达，TIL亚群和错配修复（MMR）蛋白的缺失作为MSI高的替代。我们还全面评估了这些免疫标志物、高危型人乳头瘤病毒（HPV）感染、表皮生长因子受体（EGFR）基因状态和KRAS突变之间的相互关系。在60例（45.8%）SNSCC病例中检测到PD-L1表达（肿瘤比例评分>= 1%），与总生存期（OS）较差显著相关（p = 0.0240）。高密度的分化簇8（CD 8）阳性TIL与较好的无进展生存期（PFS）显著相关（p = 0.0368），高密度的叉头盒蛋白P3阳性TIL与较好的PFS和OS显著相关（分别为p = 0.0007和0.0143）。CD 8 + TIL和PD-L1联合表达组中，CD 8/PD-L1阴性组预后最好，而CD 8/PD-L1阳性组预后最差。131例中3例（2.3%）检测到MMR丢失。HPV感染（6.1%）、EGFR突变（14.5%）、EGFR拷贝数增加（26%）和MMR丢失基本上是相互排斥的;这些分子组中的患者在预后方面显示出显著差异，但在PD-L1表达或TIL的程度方面没有差异。在9例ICI治疗的患者中，3例（33.3%）为应答者，EGFR野生型病例（n = 7）对ICI的临床应答优于EGFR突变型病例（n = 2）。在EGFR野生型肿瘤残留/复发患者中（n = 43），ICI治疗显著改善OS（p = 0.0281）。提示免疫标记物和分子分型对SNSCC患者的预后判断和个体化治疗策略的选择有一定的参考价值。
The antitumor efficacies of immune checkpoint inhibitors (ICIs) and the usefulness of potential predictive markers such as programmed death-ligand 1 (PD-L1) expression, density of tumor-infiltrating lymphocytes (TILs) and microsatellite instability (MSI) in sinonasal squamous cell carcinoma (SNSCC) have not been fully elucidated. We retrospectively analyzed 131 SNSCCs with immunohistochemistry for PD-L1 expression, TIL subpopulations and loss of mismatch repair (MMR) proteins as a surrogate for MSI-high. We also comprehensively evaluated the mutual relationships among these immuno-markers, high-risk human papillomavirus (HPV) infection, epidermal growth factor receptor (EGFR) gene status, and KRAS mutation. PD-L1 expression (tumor proportion score >= 1%) was detected in 60 (45.8%) SNSCC cases and was significantly associated with worse overall survival (OS) (p = 0.0240). High density of cluster of differentiation 8 (CD8)-positive TILs was significantly associated with better progression-free survival (PFS) (p = 0.0368), and high density of forkhead box protein P3-positive TILs was significantly associated with better PFS and OS (p = 0.0007 and 0.0143, respectively). With respect to the combination of CD8 + TIL and PD-L1 expression, the high-CD8/PD-L1-negative group showed the most favorable prognosis, whereas the low-CD8/PD-L1-positive group showed the worst prognosis. MMR loss was detected in 3 (2.3%) of the 131 cases. HPV infection (6.1%), EGFR mutation (14.5%), EGFR copy number gain (26%), and MMR loss were essentially mutually exclusive; patients in these molecular groups showed significant differences in prognosis but not in the degree of PD-L1 expression or TILs. Among the nine ICI-treated patients, three (33.3%) were responders, and the EGFR-wild type cases (n = 7) showed better clinical responses to an ICI compared to the EGFR-mutant cases (n = 2). Among the patients with residual/recurrent EGFR-wild type tumors (n = 43), ICI treatment significantly improved OS (p = 0.0281). The results suggest that the evaluation of immuno-markers and molecular subclassification may be helpful for prognostic prediction and selecting an individualized therapeutic strategy for patients with SNSCC.