PO.CL05.06 · 临床研究
使用细胞因子免疫评分验证原发性皮肤黑色素瘤中肿瘤浸润淋巴细胞的分类：解决服务不足人群中的生物标志物差异
Validating tumor-infiltrating lymphocyte classification in primary cutaneous melanoma using cytokine immune scores: Addressing biomarker disparities in underserved populations
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：免疫治疗已经改变了黑色素瘤的治疗，但其前景并未得到公平分配。生物标志物方面的差异——尤其是在肿瘤浸润淋巴细胞（TIL）分类方面——可能限制了低资源环境患者获得精准治疗的机会。将TILs通过视觉组织病理学评分分为活跃（brisk）、非活跃（non-brisk）或缺失（absent）类别仍是标准做法，但这种主观方法易受观察者间变异性的影响且缺乏标准化。这在代表性不足的非洲人群中尤其成问题，因为那里的诊断工具和分子分析资源有限。我们旨在使用基于细胞因子的免疫评分来验证传统的TIL分类，并探讨其对黑色素瘤诊疗中生物标志物公平性的意义。
方法：对来自南非患者的共205份福尔马林固定石蜡包埋（FFPE）原发性皮肤黑色素瘤样本，依据AACR定义的TIL标准进行组织学分类。使用自动化平台对肿瘤坏死因子-α（TNF-alpha）和干扰素-γ（IFN-gamma）进行免疫组织化学（IHC）染色。使用改良的Allred评分系统对细胞因子表达进行量化，该系统结合了染色强度和阳性细胞比例。通过阳性预测值（PPV）和阴性预测值（NPV）分析评估组织学TIL分类与基于细胞因子的免疫评分之间的一致性。
结果：在活跃TIL组中，TNF-alpha和IFN-gamma免疫评分的PPV分别为0.68和0.79，提示组织学表现与细胞因子激活之间存在中度至强相关。在缺失TIL组中，NPV分别为0.84（TNF-alpha）和0.91（IFN-gamma），表明与免疫静息肿瘤存在可靠的关联。然而，一部分组织学上被判定为“TIL缺失”的肿瘤却表现出强烈的细胞因子表达，凸显了生物学异质性和潜在的错误分类。这些不一致具有现实意义，尤其是在视觉判读是指导治疗的唯一可用方法的情况下。
结论：我们的发现凸显了基于细胞因子的免疫评分在验证和标准化TIL分类方面的价值。在服务不足的环境中，先进基因组检测的获取受限，纳入经济可负担且易获取的基于IHC的免疫分析可能提高诊断准确性，并扩大免疫治疗的公平可及性。随着免疫治疗资格越来越依赖于生物标志物证据，此类方法对于弥合精准肿瘤学中的差距以及解决全球癌症诊疗差异至关重要。
查看英文原文 English abstract
Background: Immunotherapy has transformed melanoma treatment, but its promise is not equitably distributed. Biomarker disparities-particularly in tumor-infiltrating lymphocyte (TIL) classification may limit access to precision treatment among patients from low-resource settings. Visual histopathologic scoring of TILs into brisk, non-brisk, or absent categories remains standard practice, but this subjective method is prone to interobserver variability and lacks standardization. This is especially problematic in underrepresented African populations, where diagnostic tools and molecular profiling resources are limited. We aimed to validate conventional TIL classification using cytokine-based immune scoring and explore its implications for biomarker equity in melanoma care.
Methods: A total of 205 formalin-fixed, paraffin-embedded (FFPE) primary cutaneous melanoma samples from South African patients were categorized histologically based on AACR-defined TIL criteria. Immunohistochemical (IHC) staining for tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) was performed using an automated platform. Cytokine expression was quantified using a modified Allred scoring system, which combines staining intensity and proportion of positive cells. Concordance between histologic TIL classification and cytokine-based immune scores was assessed through positive predictive value (PPV) and negative predictive value (NPV) analysis.
Results: In the brisk TIL group, TNF-alpha and IFN-gamma immune scores showed PPVs of 0.68 and 0.79, respectively, suggesting moderate to strong correlation between histologic appearance and cytokine activation. In the absent TIL group, NPVs were 0.84 (TNF-alpha) and 0.91 (IFN-gamma), indicating reliable association with immunologically quiescent tumors. However, a subset of histologically “TIL-absent” tumors demonstrated strong cytokine expression, highlighting biologic heterogeneity and potential misclassification. These discordances have real-world implications, especially where visual interpretation is the only method available to guide treatment.
Conclusion: Our findings underscore the value of cytokine-based immune scoring in validating and standardizing TIL classification. In underserved settings, where access to advanced genomic assays is limited, incorporating affordable and accessible IHC-based immune profiling may improve diagnostic accuracy and expand equitable access to immunotherapy. As immunotherapy eligibility increasingly depends on biomarker evidence, such approaches are essential to closing gaps in precision oncology and addressing global cancer care disparities.
利益披露 Disclosure
M. Bida, None..
R. Hull, None..
T. Miya, None..
T. Marutha, None..
Z. Dlamini, None.