Fibroblast activation protein in the tumor microenvironment predicts outcomes of PD-1 blockade therapy in advanced non-small cell lung cancer.
Fibroblast activation protein in the tumor microenvironment predicts outcomes of PD-1 blockade therapy in advanced non-small cell lung cancer.
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肿瘤微环境中的成纤维细胞激活蛋白可预测晚期非小细胞肺癌 PD-1 阻断治疗的结果
DOI：
10.1007/s00432-022-04250-4
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发表时间：
2023-07
影响因子：
3.6
通讯作者：
中科院分区：
文献类型：
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作者：
识别程序性细胞死亡 1 (PD-1) 阻断反应的稳健预测生物标志物仍然是一个关键问题。在这里，我们研究了成纤维细胞激活蛋白（FAP）作为 PD-1 阻断治疗临床结果的微环境衍生生物标志物，以及晚期非小细胞肺癌（NSCLC）中 FAP 表达与 T 细胞浸润之间的相关性。共有135例接受PD-1阻断治疗的晚期NSCLC患者进行回顾性分析。通过免疫组织化学、生物信息学分析和统计测量验证了 FAP 表达、CD3+T 细胞和 CD8+T 细胞浸润与免疫治疗临床结果之间的潜在关联。 FAP在晚期NSCLC组织中广泛表达。 FAP 与 CD8+T 细胞密度降低（Spearman’s rho – 0.32，p< 0.001）和免疫抑制肿瘤微环境 (TME) 状态相关。未检测到 FAP 和 PD-L1 表达或与 CD3 + T 细胞密度之间的相关性。 FAP表达较高的患者表现出较差的缓解率（16.4% vs. 38.7%，p<0.001）和较差的无进展生存期（HR = 2.56，95% CI 1.69–3.87，p< 0.001）。此外，FAP 导致鳞状细胞肺癌 (p = 0.020)、PD-1 阻断单药治疗 (p = 0.017) 和一线治疗 (p = 0.028) 患者亚组的总生存期缩短。 FAP 是 PD-1 阻断耐药性的潜在预测生物标志物。需要进一步研究以确定针对 FAP 的策略，以减轻免疫抑制性 TME 并扩大 PD-1 阻断疗法的临床有效性。在线版本包含可在 10.1007/s00432-022-04250-4 获取的补充材料。
The identification of robust predictive biomarkers of the response to programmed cell death-1 (PD-1) blockade remains a critical concern. Here, we investigated on fibroblast activation protein (FAP) as a microenvironment-derived biomarker of clinical outcomes of PD-1 blockade therapy, and the correlation between FAP expression and T cell infiltration in advanced non-small cell lung cancer (NSCLC). A total of 135 patients with advanced NSCLC who received PD-1 blockade therapy were retrospectively analyzed. The potential associations among FAP expression, CD3 + T cell and CD8 + T cell infiltration, and clinical outcomes of immunotherapy were validated by immunohistochemistry, bioinformatic analyses, and statistical measurements. FAP was widely expressed in advanced NSCLC tissues. FAP was correlated with decreased density of CD8 + T cells (Spearman’s rho – 0.32, p < 0.001) and immunosuppressive tumor microenvironment (TME) status. No correlations were detected between FAP and PD-L1 expression or with the density of CD3 + T cells. The patients with higher expression of FAP showed worse response rate (16.4% vs. 38.7%, p < 0.001) and worse progression-free survival (HR = 2.56, 95% CI 1.69–3.87, p < 0.001). In addition, FAP contributed to shortened overall survival in subgroups of the patients with squamous cell lung cancer (p = 0.020), PD-1 blockade monotherapy (p = 0.017), and first-line therapy (p = 0.028). FAP is a potential predictive biomarker of resistance to PD-1 blockade. Further investigation is warranted to identify a strategy for targeting FAP to alleviate the immunosuppressive TME and broaden the clinical effectiveness of PD-1 blockade therapy. The online version contains supplementary material available at 10.1007/s00432-022-04250-4.
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