Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.
Department of Bioinformatics Devision, The Walter and Eliza Hall Institute, Melbourne, VIC, Australia.
Front Immunol. 2023 Apr 3;14:1135489. doi: 10.3389/fimmu.2023.1135489. eCollection 2023.
Mucosal head and neck squamous cell carcinoma (HNSCC) are the seventh most common cancer, with approximately 50% of patients living beyond 5 years. Immune checkpoint inhibitors (ICIs) have shown promising results in patients with recurrent or metastatic (R/M) disease, however, only a subset of patients benefit from immunotherapy. Studies have implicated the tumor microenvironment (TME) of HNSCC as a major factor in therapy response, highlighting the need to better understand the TME, particularly by spatially resolved means to determine cellular and molecular components. Here, we employed targeted spatial profiling of proteins on a cohort of pre-treatment tissues from patients with R/M disease to identify novel biomarkers of response within the tumor and stromal margins. By grouping patient outcome categories into response or non-response, based on Response Evaluation Criteria in Solid Tumors (RECIST) we show that immune checkpoint molecules, including PD-L1, B7-H3, and VISTA, were differentially expressed. Patient responders possessed significantly higher tumor expression of PD-L1 and B7-H3, but lower expression of VISTA. Analysis of response subgroups indicated that tumor necrosis factor receptor (TNFR) superfamily members including OX40L, CD27, 4-1BB, CD40, and CD95/Fas, were associated with immunotherapy outcome. CD40 expression was higher in patient-responders than non responders, while CD95/Fas expression was lower in patients with partial response (PR) relative to those with stable disease (SD) and progressive disease (PD). Furthermore, we found that high 4-1BB expression in the tumor compartment, but not in the stroma, was associated with better overall survival (OS) (HR= 0.28, p-adjusted= 0.040). Moreover, high CD40 expression in tumor regions (HR= 0.27, p-adjusted= 0.035), and high CD27 expression in the stroma (HR= 0.2, p-adjusted=0.032) were associated with better survival outcomes. Taken together, this study supports the role of immune checkpoint molecules and implicates the TNFR superfamily as key players in immunotherapy response in our cohort of HNSCC. Validation of these findings in a prospective study is required to determine the robustness of these tissue signatures.
黏膜头颈部鳞状细胞癌（HNSCC）是第七大常见癌症，约有 50%的患者生存时间超过 5 年。免疫检查点抑制剂（ICIs）在复发性或转移性（R/M）疾病患者中显示出良好的疗效，但只有一部分患者受益于免疫治疗。研究表明，HNSCC 的肿瘤微环境（TME）是治疗反应的一个主要因素，这突显了需要更好地了解 TME，特别是通过空间分辨手段来确定细胞和分子成分。在这里，我们对 R/M 疾病患者的预处理组织进行了靶向空间蛋白质谱分析，以确定肿瘤和基质边缘的新的反应标志物。通过根据实体瘤反应评估标准（RECIST）将患者的预后类别分为反应或非反应，我们发现免疫检查点分子，包括 PD-L1、B7-H3 和 VISTA，表达不同。患者反应者的肿瘤 PD-L1 和 B7-H3 表达显著升高，但 VISTA 表达较低。对反应亚组的分析表明，肿瘤坏死因子受体（TNFR）超家族成员，包括 OX40L、CD27、4-1BB、CD40 和 CD95/Fas，与免疫治疗结果相关。与非反应者相比，患者反应者的肿瘤 CD40 表达更高，而 CD95/Fas 表达在部分反应（PR）患者中低于稳定疾病（SD）和进展疾病（PD）患者。此外，我们发现肿瘤部位的 4-1BB 高表达（HR=0.28，p 调整=0.040）与总生存（OS）更好相关，而基质中的 4-1BB 高表达与更好的 OS 无关。此外，肿瘤区域的 CD40 高表达（HR=0.27，p 调整=0.035）和基质中的 CD27 高表达（HR=0.2，p 调整=0.032）与更好的生存结果相关。总之，这项研究支持免疫检查点分子的作用，并表明 TNFR 超家族是我们 HNSCC 队列中免疫治疗反应的关键参与者。需要在前瞻性研究中验证这些发现，以确定这些组织特征的稳健性。
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