Background:Immune checkpoint inhibitors (ICIs) have revolutionized non-small cell lung cancers (NSCLCs) treatment, but only 20–30% of patients benefit from these treatments. Currently, PD-L1 expression in tumor cells is the only clinically approved predictor of ICI response in lung cancer, but concerns arise due to its low negative and positive predictive value. Recent studies suggest that CXCL13+ T cells in the tumor microenvironment (TME) may be a good predictor of response. We aimed to assess if CXCL13+ cell localization within the TME can predict ICI response in advanced NSCLC patients.Methods:This retrospective study included 65 advanced NSCLC patients treated with Nivolumab/Pembrolizumab at IUCPQ or CHUM and for whom a pretreatment surgical specimen was available. Good responders were defined as having a complete radiologic response at 1 year, and bad responders were defined as showing cancer progression at 1 year. IHC staining for CXCL13 was carried out on a representative slide from a resection specimen, and CXCL13+ cell density was evaluated in tumor (T), invasive margin (IM), non-tumor (NT), and tertiary lymphoid structure (TLS) compartments. Cox models were used to analyze progression-free survival (PFS) and overall survival (OS) probability, while the Mann–Whitney test was used to compare CXCL13+ cell density between responders and non-responders.Results:We showed that CXCL13+ cell density localization within the TME is associated with ICI efficacy. An increased density of CXCL13+ cells across all compartments was associated with a poorer prognostic (OS; HR = 1.22; 95%CI = 1.04–1.42;p= 0.01, PFS; HR = 1.16;p= 0.02), or a better prognostic when colocalized within TLSs (PFS; HR = 0.84,p= 0.03).Conclusion:Our results support the role of CXCL13+ cells in advanced NSCLC patients, with favorable prognosis when localized within TLSs and unfavorable prognosis when present elsewhere. The concomitant proximity of CXCL13+ and CD20+ cells within TLSs may favor antigen presentation to T cells, thus enhancing the effect of PD-1/PD-L1 axis inhibition. Further validation is warranted to confirm the potential relevance of this biomarker in a clinical setting.
背景：免疫检查点抑制剂（ICIs）已彻底改变非小细胞肺癌（NSCLC）的治疗格局，但仅有20-30%的患者能从该疗法中获益。目前，肿瘤细胞中的PD-L1表达是临床上唯一获批的肺癌ICI疗效预测指标，但其阴性预测值与阳性预测值均较低，引发学界担忧。近期研究表明，肿瘤微环境（TME）中的CXCL13+ T细胞可能是更有效的预测标志物。本研究旨在评估TME中CXCL13+细胞的定位特征能否预测晚期NSCLC患者的ICI治疗反应。 方法：本回顾性研究纳入65例在IUCPQ或CHUM中心接受纳武利尤单抗/帕博利珠单抗治疗且留存治疗前手术标本的晚期NSCLC患者。疗效良好组定义为治疗1年时达到完全影像学缓解，疗效不佳组定义为治疗1年时出现疾病进展。对切除标本的代表性切片进行CXCL13免疫组化染色，分别在肿瘤核心区（T）、侵袭边缘区（IM）、非肿瘤区（NT）及三级淋巴结构（TLS）内评估CXCL13+细胞密度。采用Cox模型分析无进展生存期（PFS）与总生存期（OS）概率，使用Mann-Whitney检验比较不同疗效组间的CXCL13+细胞密度差异。 结果：研究发现TME中CXCL13+细胞的定位分布与ICI疗效相关。所有分区中CXCL13+细胞密度升高均提示不良预后（OS：HR=1.22，95%CI=1.04-1.42，p=0.01；PFS：HR=1.16，p=0.02），但当CXCL13+细胞共定位于TLS内时则预示更好预后（PFS：HR=0.84，p=0.03）。 结论：本研究证实CXCL13+细胞在晚期NSCLC中具有双重预后价值：定位于TLS内时提示良好预后，分布于其他区域时则提示不良预后。TLS内CXCL13+细胞与CD20+细胞的邻近分布可能促进抗原递呈至T细胞，从而增强PD-1/PD-L1轴抑制效应。该生物标志物的临床潜在价值仍需进一步验证。
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