HIF-1α、PD-L1与非小细胞肺癌淋巴转移的相关性

doi:10.3877/cma.j.issn.1674-6902.2020.02.023

目的

探讨HIF-1α、PD-L1表达水平与非小细胞肺癌(NSCLC)患者淋巴转移风险的相关性。

方法

选择2015年12月至2017年12月于我院手术治疗且未发生淋巴结转移的NSCLC患者97例。免疫组化分析对所有患者癌症病灶中HIF-1α、PD-L1的表达量进行检测。而后进行为期24月的随访，记录淋巴转移发生情况。根据HIF-1α及PD-L1表达量对所有患者进行分组，分析随访期间两种蛋白不同表达量患者淋巴转移风险之间的差异。通过COX回归分析确定NSCLC淋巴结转移之间的危险因素。

结果

所有患者平均随访时间19(12，24)月，共计92例患者完成随访，发生淋巴结转移例数36例，淋巴结转移率39.13%，淋巴结未转移中位时间时间24(16，24)月。HIF-1α高表达及低表达患者淋巴结转移率巴结转移发生率分别为92.6%和26.9%，HIF-1α高表达患者淋巴结转移率显著高于低表达患者(log-rankχ²＝63.052；P<0.001)。PD-L1高表达及低表达患者淋巴结转移发生率分别为82.1%和21.3%，PD-L1高表达患者淋巴结转移率显著高于低表达患者(log-rankχ²＝39.555；P<0.001)。HIF-1α高表达(HR＝25.790，95%CI＝10.005-30.287)、PD-L1高表达(HR＝16.693，95%CI＝12.014-20.356)、CEA(HR＝1.058，95%CI＝1.013-1.106)是NSCLC患者淋巴转移的危险因素(P<0.05)。

结论

HIF-1α、PD-L1高表达与NSCLC患者淋巴转移风险具有显著相关性，可作为早期预测和治疗的靶点。

关键词: HIF-1α, PD-L1, 非小细胞肺癌, 淋巴结转移

Objective

To investigate the correlation between the expression levels of HIF-1α and PD-L1 and the risk of lymphatic metastasis in patients with non-small cell lung cancer (NSCLC).

Methods

A total of 97 NSCLC patients who underwent surgical treatment in our hospital from December 2015 to December 2017 without lymph node metastasis were selected. Immunohistochemical analysis was used to detect the expression of HIF-1α and PD-L1 in cancer lesions of all patients. Then a follow-up period of 24 months was performed to record the occurrence of lymphatic metastases. All patients were grouped according to the expression levels of HIF-1α and PD-L1, and the differences in the risk of lymphatic metastasis in patients with different expression levels of the two proteins during the follow-up period were analyzed. COX regression analysis was used to determine the relationship between HIF-1α and PD-L1 and NSCLC lymph node metastasis.

Results

All patients were followed up for an average of 19 (12, 24) months. A total of 92 patients completed the follow-up. 36 cases of lymph node metastasis occurred. The rate of lymph node metastasis was 39.13%. Lymph node metastasis rates in patients with high and low expression of HIF-1α were 92.6% and 26.9%, respectively. Lymph node metastasis rates in patients with high expression of HIF-1α were significantly higher than those in patients with low expression (log-rankχ²=63.052; P<0.001) . The incidence of lymph node metastasis in patients with high PD-L1 expression and low expression was 82.1% and 21.3%, respectively. The lymph node metastasis rate in patients with high PD-L1 expression was significantly higher than that in patients with low expression (log-rankχ²=39.555; P<0.001). HIF-1α high expression (HR=25.790, 95%CI=10.005-30.287), PD-L1 high expression (HR=16.693, 95%CI=12.014-20.356), CEA (HR=1.058, 95%CI=1.013-1.106) is a risk factor for lymphatic metastasis in patients with NSCLC (P<0.05).

Conclusion

The high expression of HIF-1α and PD-L1 has significant correlation with the risk of lymphatic metastasis in patients with NSCLC, and can be used as targets for early prediction and treatment.

Key words: HIF-1α, PD-L1, Non-small cell lung cancer, Lymph node metastasis

图1 HIF-1α表达量对于NSCLC患者淋巴结转移的影响

图2 PD-L1表达量对于NSCLC患者淋巴结转移的影响

表1 NSCLC患者淋巴结转移的影响因素分析

临床资料		转移(n＝36)	非转移(n＝56)	HR(95%CI)	P值
年龄(岁)		56.85±12．73	55.58±10．31	1.007(0.977～1.038)	0.657
性别构成(男/女)		17/21	24/22	1.116(0.603～2.232)	0.657
BMI(kg/m²)		20.81±2．41	21.49±1．92	0.899(0.796～1.052)	0.185
HIF-1α
	低表达	11	54	10.324(4.985～21.380)	<0.001
	高表达	25	2
PD-L1
	低表达	13	51	6.896(3.449～13.789)	<0.001
	高表达	23	5
TMN分期
	Ⅰ	9	32	2.952(1.387～6.285)	0.005
	Ⅱ	27	24
病理分型
	腺癌	24	41	1.188(0.594～2.377)	0.626
	非腺癌	12	15
CEA(ng/ml)		159.84±19．93	141.83±20．29	1.028(1.013～1.043)	<0.001
肿瘤直径(cm)		3.68±1．12	2.68±1．10	1.712(1.286～2.279)	<0.001
影像学特征
	毛刺征	14	21	1.094(0.559～2.138)	0.793
	血管集束征	6	14	0.715(0.298～1.719)	0.454
	胸膜凹陷	10	19	1.527(0.736～3.168)	0.255
	空洞	7	19	0.532(0.233～1.216)	0.135
	支气管血管束增厚	4	10	1.098(0.481～2.507)	0.824
病灶位置(左右肺)
	左肺	21	33	0.995(0.513～1.930)	0.995
	右肺	15	23
病灶分叶
	上叶	19	31	0.953(0.495～1.834)	0.885
	中、下叶	17	25

表1 NSCLC患者淋巴结转移的影响因素分析

临床资料		转移(n＝36)	非转移(n＝56)	HR(95%CI)	P值
年龄(岁)		56.85±12．73	55.58±10．31	1.007(0.977～1.038)	0.657
性别构成(男/女)		17/21	24/22	1.116(0.603～2.232)	0.657
BMI(kg/m²)		20.81±2．41	21.49±1．92	0.899(0.796～1.052)	0.185
HIF-1α
	低表达	11	54	10.324(4.985～21.380)	<0.001
	高表达	25	2
PD-L1
	低表达	13	51	6.896(3.449～13.789)	<0.001
	高表达	23	5
TMN分期
	Ⅰ	9	32	2.952(1.387～6.285)	0.005
	Ⅱ	27	24
病理分型
	腺癌	24	41	1.188(0.594～2.377)	0.626
	非腺癌	12	15
CEA(ng/ml)		159.84±19．93	141.83±20．29	1.028(1.013～1.043)	<0.001
肿瘤直径(cm)		3.68±1．12	2.68±1．10	1.712(1.286～2.279)	<0.001
影像学特征
	毛刺征	14	21	1.094(0.559～2.138)	0.793
	血管集束征	6	14	0.715(0.298～1.719)	0.454
	胸膜凹陷	10	19	1.527(0.736～3.168)	0.255
	空洞	7	19	0.532(0.233～1.216)	0.135
	支气管血管束增厚	4	10	1.098(0.481～2.507)	0.824
病灶位置(左右肺)
	左肺	21	33	0.995(0.513～1.930)	0.995
	右肺	15	23
病灶分叶
	上叶	19	31	0.953(0.495～1.834)	0.885
	中、下叶	17	25

表2 影响淋巴结转移的Cox回归分析结果

因　素	β	标准误	Wald	P值	HR	95%CI
因　素	β	标准误	Wald	P值	HR	LL	UL
HIF-1α高表达	3.25	1.021	10.138	0.001	25.790	10.005	30.287
PD-L1高表达	2.815	0.909	9.599	0.002	16.693	12.014	20.356
CEA	0.057	0.022	6.42	0.011	1.058	1.013	1.106

表2 影响淋巴结转移的Cox回归分析结果

因　素	β	标准误	Wald	P值	HR	95%CI
因　素	β	标准误	Wald	P值	HR	LL	UL
HIF-1α高表达	3.25	1.021	10.138	0.001	25.790	10.005	30.287
PD-L1高表达	2.815	0.909	9.599	0.002	16.693	12.014	20.356
CEA	0.057	0.022	6.42	0.011	1.058	1.013	1.106

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Correlation between HIF-1α, PD-L1 and lymphatic metastasis in non-small cell lung cancer

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Correlation between HIF-1α, PD-L1 and lymphatic metastasis in non-small cell lung cancer