在非小细胞肺癌中，PD-1/PD-L1复合物而不是PD-L1的表达高度预测患者对免疫治疗的反应

SCI 12 March 2023

Functional Engagement of the PD-1/PD-L1 Complex But Not PD-L1 Expression Is Highly Predictive of Patient Response to Immunotherapy in Non–Small-Cell Lung Cancer

（J Clin Oncol；IF：50.717）

Sánchez-Magraner L, Gumuzio J, Miles J, Quimi N, Martínez Del Prado P, Abad-Villar MT et al. Functional Engagement of the PD-1/PD-L1 Complex But Not PD-L1 Expression Is Highly Predictive of Patient Response to Immunotherapy in Non-Small-Cell Lung Cancer. J Clin Oncol 2023:Jco2201748.

CORRESPONDENCE TO: V´eronique Calleja, PhD, HAWK Biosystems (FASTBASE Solutions S.L)., 612 Astondo Bidea, Science and Technology Park of Bizkaia, Derio, Bizkaia 48160, Spain; e-mail: veronique.calleja@hawkbiosystems.com.

PURPOSE 目的  

In many cancers, the expression of immunomodulatory ligands leads to immunoevasion, as exemplified by the interaction of PD-L1 with PD-1 on tumor-infiltrating lymphocytes. Profound advances in cancer treatments have come with the advent of immunotherapies directed at blocking these immuno-suppressive ligand-receptor interactions. However, although there has been success in the use of these immune checkpoint interventions, correct patient stratification for these therapies has been challenging.

在许多癌症中，免疫调节配体的表达导致免疫逃避，如PD-L1与PD-1在肿瘤浸润淋巴细胞上的相互作用。随着免疫疗法的出现，癌症治疗取得了很大的进展，这些疗法旨在阻断这些免疫抑制配体-受体相互作用。然而，尽管这些免疫检查点干预措施的使用已经取得了成功，但寻找这些疗法的最佳患者一直具有挑战性。

MATERIALS AND METHODS 方法

To address this issue of patient stratification, we have quantified the intercellular PD-1/PD-L1 interaction in formalin-fixed paraffin-embedded tumor samples from patients with non–small cell lung carcinoma, using a high-throughput automated quantitative imaging platform (quantitative functional proteomics [QF-Pro]).

为了解决患者分层的这一问题，我们使用高通量自动化定量成像平台(定量功能蛋白组学[QF-Pro])，定量了非小细胞肺癌患者福尔马林固定石蜡包埋肿瘤样本中PD-1/PD-L1的细胞间相互作用。

RESULTS 结果  

The multisite blinded analysis across a cohort of 188 immune checkpoint inhibitor-treated patients demonstrated the intra- and intertumoral heterogeneity of PD-1/PD-L1 immune checkpoint engagement and notably showed no correlation between the extent of PD-1/PD-L1 interaction and PD-L1 expression. Importantly, PD-L1 expression scores used clinically to stratify patients correlated poorly with overall survival; by contrast, patients showing a high PD-1/PD-L1 interaction had significantly better responses to anti–PD-1/PD-L1 treatments, as evidenced by increased overall survival. This relationship was particularly strong in the setting of first-line treatments.

对188例免疫检查点抑制剂治疗患者的盲法分析证实了PD-1/PD-L1免疫检查点治疗的瘤内和瘤间异质性，值得注意的是，PD-1/PD-L1相互作用的程度与PD-L1表达之间没有相关性。重要的是，临床用于患者分层的PD-L1表达评分与总生存期相关性较差;相比之下，高PD-1/PD-L1相互作用的患者对PD-1/PD-L1治疗有明显更好的反应，总生存期增加就是证明。这种关系在一线治疗中尤其明显。

CONCLUSION 结论  

The functional readout of PD-1/PD-L1 interaction as a predictive biomarker for the stratification of patients with non–small-cell lung carcinoma, combined with PD-L1 expression, should significantly improve the response rates to immunotherapy. This would both capture patients excluded from checkpoint immunotherapy (high PD-1/PD-L1 interaction but low PD-L1 expression, 24% of patients) and additionally avoid treating patients who despite their high PD-L1 expression do not respond and suffer from side effects.

PD-1/PD-L1相互作用作为非小细胞肺癌患者分层的预测性生物标志物，结合PD-L1表达，可以显著提高对免疫治疗的反应率。这既可以确定被排除在检查点免疫治疗之外的患者(高PD-1/PD-L1相互作用但低PD-L1表达，24%的患者)，也可以避免治疗尽管PD-L1高表达但无反应且有副作用的患者。

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