Sharma G, Baca Y, Shields A F, Prakash A, Weinberg B A, Saeed A, Goel S, Abdalla A, Oberley M, Xiu J, Hwang J, Antonarakis E S, Chiu V K, Lou E
Division of Hematology and Medical Oncology, Mitchell Cancer Institute, University of South Alabama, Mobile, USA.
CARIS Life Sciences, Phoenix, USA.
ESMO Open. 2025 Jun;10(6):105315. doi: 10.1016/j.esmoop.2025.105315. Epub 2025 Jun 10.
Anal squamous-cell carcinoma (ASCC) is a rare cancer. Immune checkpoint inhibitors (ICIs) are used as a second-line treatment. We aimed to analyze the genomic and transcriptomic profiles of ASCC to predict ICI efficacy.
Next-generation sequencing (NGS) of DNA and RNA was carried out. Programmed death- ligand 1 (PD-L1) expression was tested by immunohistochemistry (IHC) as high (≥2+ and ≥5%), low (1-2+ and ≥1%), and negative (<1). Deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) was tested using IHC/NGS, and tumor mutation burden-high (TMB-H) was defined as ≥10 mutations/Mb. quanTIseq was used to quantify tumor microenvironment. The chi-square test / Fisher's exact test was used, and significance was determined as P value adjusted for multiple comparisons (q < 0.05). Real-world overall survival and time on treatment (TOT) were obtained from insurance claims.
Out of 1242 tumor samples, 64.25% expressed PD-L1, with 41.7% exhibiting high expression. TMB-H and dMMR/MSI-H prevalence rates were 11.43% and 1.04%, respectively. TMB-H tended to be higher in PD-L1-low versus PD-L1-negative patients (P = 0.03). Mutations in PIK3CA and CASP8 were significantly higher in PD-L1-high versus -negative. PD-L1-high tumor microenvironment showed higher infiltration of Tregs, M1 macrophages, neutrophils, CD8 cells, and cancer-associated fibroblasts compared with PD-L1-low (q < 0.05). The expression of immuno-oncology (IO) markers, including IDO1, PDCD1, IFNG, CD274, HVACR2, CTLA4, LAG3, CD80, CD86, and PDCD1LG2, as well as T-cell inflammation and interferon-gamma scores, exhibited a concurrent decline in association with PD-L1 expression. The PD-L1-high group treated with ICIs had significantly longer TOT than the PD-L1-negative group (hazard ratio 0.758, 95% confidence interval 0.579-0.992, P = 0.044).
PD-L1-expressing ASCCs exhibit higher rates of PIK3CA and CASP8 mutations, increased IO markers, and higher inflammation. These tumors had longer treatment durations when treated with ICIs, suggesting that PD-L1 expression predicts treatment response.
肛管鳞状细胞癌（ASCC）是一种罕见的癌症。免疫检查点抑制剂（ICI）用作二线治疗。我们旨在分析ASCC的基因组和转录组图谱，以预测ICI疗效。
对DNA和RNA进行下一代测序（NGS）。通过免疫组织化学（IHC）检测程序性死亡配体1（PD-L1）表达，分为高表达（≥2+且≥5%）、低表达（1-2+且≥1%）和阴性（<1%）。使用IHC/NGS检测错配修复缺陷/微卫星高度不稳定（dMMR/MSI-H），肿瘤突变负荷高（TMB-H）定义为≥10个突变/Mb。使用quanTIseq对肿瘤微环境进行定量。采用卡方检验/费舍尔精确检验，显著性以经多重比较调整后的P值确定（q<0.05）。从保险理赔中获取真实世界的总生存期和治疗时间（TOT）。
在1242个肿瘤样本中，64.25%表达PD-L1，其中41.7%为高表达。TMB-H和dMMR/MSI-H的患病率分别为11.43%和1.04%。与PD-L1阴性患者相比，PD-L1低表达患者的TMB-H往往更高（P=0.03）。与PD-L1阴性相比，PIK3CA和CASP8突变在PD-L1高表达中显著更高。与PD-L1低表达相比，PD-L1高表达的肿瘤微环境显示调节性T细胞、M1巨噬细胞、中性粒细胞、CD8细胞和癌症相关成纤维细胞的浸润更高（q<0.05）。免疫肿瘤学（IO）标志物，包括吲哚胺2,3-双加氧酶1（IDO1）、程序性死亡受体1（PDCD1）、干扰素γ（IFNG）、CD274、HVACR2、细胞毒性T淋巴细胞相关蛋白4（CTLA4）、淋巴细胞激活基因3（LAG3）、CD80、CD86和程序性死亡配体1B（PDCD1LG2）的表达，以及T细胞炎症和干扰素γ评分，与PD-L1表达呈同步下降。接受ICI治疗的PD-L1高表达组的TOT显著长于PD-L1阴性组（风险比0.758，95%置信区间0.579-0.992，P=0.044）。
表达PD-L1的ASCC显示出更高的PIK3CA和CASP8突变率、增加的IO标志物和更高的炎症。这些肿瘤接受ICI治疗时的治疗持续时间更长，表明PD-L1表达可预测治疗反应。
