Economopoulou P, Rampias T, Spathis A, Kotsantis I, Kyriazoglou A, Anastasiou M, Pantazopoulos A, Gomatou G, Margeli A, Papageorgiou M, Foukas P, Psyrri A
Oncology Unit, 2nd Department of Internal Medicine, National and Kapodistrian University of Athens, Attikon University Hospital, Haidari, Greece.
Biomedical Research Foundation Academy of Athens, Athens, Greece.
ESMO Open. 2025 Aug 12;10(8):105538. doi: 10.1016/j.esmoop.2025.105538.
BACKGROUND: HRAS mutations define a distinct biologic subset of head and neck squamous-cell carcinoma (HNSCC). There are limited data regarding HRAS-mutant (mut) tumors' sensitivity to immunotherapy. We sought to evaluate the mutational landscape and transcriptional profile, as well as analyze the tumor microenvironment (TME) of HRAS-mut tumors to provide the conceptual framework for combinatorial treatment approaches. MATERIALS AND METHODS: We analyzed mutational and transcriptome data from The Cancer Genome Atlas (TCGA). In addition, genomic DNA from baseline tumor biopsies was targeted for sequencing. Our study included 10 patients with HRAS-mut and 40 with HRAS-wild-type (WT) HNSCC. Programmed death-ligand 1 (PD-L1) expression in formalin-fixed paraffin-embedded tumor samples was assessed using the PD-L1 IHC 22C3 pharmDx assay. We characterized subpopulations of exhausted CD8(+) T cells by measuring the expression of T-cell factor-1 (TCF1) and programmed cell death protein 1 (PD-1) in both the center and the periphery of the tumors using multiplex immunohistochemistry, followed by analysis using a manually trained algorithm in QuPath software. RESULTS: The analysis of TCGA HNSCC mutation and mRNA expression data demonstrated that 6% of HNSCCs harbor mutant HRAS. Transcriptome analysis showed that HRAS-mut HNSCCs are infiltrated by immune cells (CD8A, CD8B, CD2) and have higher expression levels of CXCL11, CXCL10, CXCL9 and CCL4 chemokines. Moreover, the percentage of HRAS-mut samples increased in higher PD-L1 score groups (11% versus 20% versus 100% in tumor positive scores <1%, 1%-49% and ≥50%, respectively, P = 0.006). The analysis of TME showed that HRAS-mut tumors have a statistically significant higher number of total immune cells (5123.17/mm versus 3527.93/mm, P = 0.002) and a higher percentage of pre-exhausted CD8(+) PD-1(+) TCF1(+) T cells in the periphery (384.67/mm versus 51.18/mm, P = 0.040) than HRAS-WT tumors. CONCLUSIONS: HRAS-mut HNSCCs are characterized by a significantly increased number of pre-exhausted PD-1(+) TCF1(+) T cells and PD-L1 expression, suggesting a potential sensitivity to immunotherapy.
背景：HRAS 突变定义了头颈部鳞状细胞癌（HNSCC）的一个独特生物学亚群。关于 HRAS 突变（mut）肿瘤对免疫疗法的敏感性数据有限。我们试图评估 mut 肿瘤的突变图谱和转录谱，并分析其肿瘤微环境（TME），以为联合治疗方法提供概念框架。 材料与方法：我们分析了来自癌症基因组图谱（TCGA）的突变和转录组数据。此外，对基线肿瘤活检组织的基因组 DNA 进行靶向测序。我们的研究纳入了 10 例 HRAS 突变型和 40 例 HRAS 野生型（WT）HNSCC 患者。使用 PD-L1 IHC 22C3 免疫组化检测法评估福尔马林固定石蜡包埋肿瘤样本中程序性死亡配体 1（PD-L1）的表达。我们通过使用多重免疫组化测量肿瘤中心和周边 T 细胞转录因子 1（TCF1）和程序性细胞死亡蛋白 1（PD-1）的表达来表征耗竭性 CD8(+) T 细胞亚群，随后使用 QuPath 软件中的手动训练算法进行分析。 结果：对 TCGA HNSCC 突变和 mRNA 表达数据的分析表明，6%的 HNSCC 携带突变型 HRAS。转录组分析显示，HRAS 突变型 HNSCC 被免疫细胞（CD8A、CD8B、CD2）浸润，并且 CXCL11、CXCL10、CXCL9 和 CCL4 趋化因子的表达水平更高。此外，在较高 PD-L1 评分组中，HRAS 突变样本的百分比增加（肿瘤阳性评分<1%、1%-49%和≥50%时分别为 11%、20%和 100%，P = 0.006）。对 TME 的分析表明，与 HRAS 野生型肿瘤相比，HRAS 突变型肿瘤的总免疫细胞数量在统计学上显著更高（分别为 5123.17/mm 和 3527.93/mm，P = 0.002），并且周边预耗竭的 CD8(+) PD-1(+) TCF1(+) T 细胞百分比更高（分别为 384.67/mm 和 51.18/mm，P = 0.040）。 结论：HRAS 突变型 HNSCC 的特征是预耗竭的 PD-1(+) TCF1(+) T 细胞数量和 PD-L1 表达显著增加，提示对免疫疗法可能敏感。
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