骨转移会削弱免疫检查点抑制剂在非小细胞肺癌中的疗效，并呈现出“冷”免疫特征。
Bone metastasis attenuates efficacy of immune checkpoint inhibitors and displays "cold" immune characteristics in Non-small cell lung cancer.
作者信息
Zhu Yan-Juan, Chang Xue-Song, Zhou Rui, Chen Ya-Dong, Ma Hao-Chuan, Xiao Zhen-Zhen, Qu Xin, Liu Yi-Hong, Liu Li-Rong, Li Yong, Yu Ya-Ya, Zhang Hai-Bo
机构信息
Department of Oncology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Department of Oncology, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, China.
Department of Oncology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Department of Oncology, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, China.
出版信息
Lung Cancer. 2022 Apr;166:189-196. doi: 10.1016/j.lungcan.2022.03.006. Epub 2022 Mar 10.
OBJECTIVES
This study aimed to assess the clinical characteristics affecting outcomes after immune checkpoint inhibitors (ICI) therapies in non-small cell lung cancer (NSCLC) patients, and the underlying mechanism in tumor immune micro-environment (TIME).
MATERIALS AND METHODS
A total of 144 patients treated with ICI-based strategies were retrospectively analyzed. Expression of 10 immune antibodies in tumor tissues from other 60 untreated NSCLC patients were sequentially tested using multiplexed immunofluorescence (mIF) staining method. Correlation of clinical characteristics with ICI treatment outcomes and TIME characteristics were analyzed.
RESULTS
Multivariate logistic and cox regression indicated that BoM negatively affected disease control rate (OR = 0.32, 95%CI: 0.13-0.82, P = 0.018), progression free survival (HR = 3.44, 95% CI:1.97-6.00, P < 0.001) and overall survival (HR = 3.24, 95% CI:1.62-6.50, P = 0.001), irrespective of programmed death-ligand 1 (PD-L1) expression. BoM patients were with significantly lower PD-L1, and this heterogeneity of TIME was then confirmed in the mIF staining, where 36 (61.0%) patients were clustered into immune-subtype A, with low expression of all the detected immune markers, similar to "cold" tumors, and 23 (39.0%) in cluster B with likely "hot" tumors. More patients in immune-subtype A were non-smokers (63.9% vs. 39.1% P = 0.063), with BoM (66.7% vs. 21.7%, P = 0.001), in stage IV(88.9% vs. 65.2%, P = 0.045), and with adenocarcinoma (91.7% vs. 69.6%, P = 0.037). Multivariate logistic regression indicated that BoM was independently associated with the "cold" immune characteristics (OR = 0.19, 95% CI:0.04-0.84, P = 0.028). Combination therapy with chemotherapy /antiangiogenesis or use of bisphosphonate during ICI treatment significantly improved clinical outcomes in BoM patients.
CONCLUSIONS
BoM displays adverse impact on clinical outcomes after ICI treatments in NSCLC patients. The "cold" characteristics of TIME may be the underlying mechanism for the attenuated efficacy of ICIs in bone metastatic NSCLC patients.
目的
本研究旨在评估影响非小细胞肺癌（NSCLC）患者接受免疫检查点抑制剂（ICI）治疗后疗效的临床特征，以及肿瘤免疫微环境（TIME）中的潜在机制。
材料与方法
回顾性分析了144例接受基于ICI策略治疗的患者。使用多重免疫荧光（mIF）染色方法依次检测另外60例未经治疗的NSCLC患者肿瘤组织中10种免疫抗体的表达。分析临床特征与ICI治疗疗效及TIME特征的相关性。
结果
多因素逻辑回归和Cox回归表明，骨转移（BoM）对疾病控制率有负面影响（OR = 0.32，95%CI：0.13 - 0.82，P = 0.018），无进展生存期（HR = 3.44，95%CI：1.97 - 6.00，P < 0.001）和总生存期（HR = 3.24，95%CI：1.62 - 6.50，P = 0.001），与程序性死亡配体1（PD-L1）表达无关。BoM患者的PD-L1显著较低，这种TIME的异质性在mIF染色中得到证实，其中36例（61.0%）患者被归为免疫亚型A，所有检测的免疫标志物表达均较低，类似于“冷”肿瘤，23例（39.0%）归为B簇，可能为“热”肿瘤。免疫亚型A中更多患者为非吸烟者（63.9%对39.1%，P = 0.063），有BoM（66.7%对2l.7%，P = 0.001），处于IV期（88.9%对65.2%，P = 0.045），且为腺癌（91.7%对69.6%，P = 0.037）。多因素逻辑回归表明，BoM与 “冷”免疫特征独立相关（OR = 0.19，95%CI：0.04 - 0.84，P = 0.028）。ICI治疗期间联合化疗/抗血管生成或使用双膦酸盐可显著改善BoM患者的临床疗效。
结论
BoM对NSCLC患者ICI治疗后的临床疗效有不利影响。TIME的“冷”特征可能是ICI在骨转移NSCLC患者中疗效减弱的潜在机制。
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