炎症标志物的变化趋势对一线接受免疫联合化疗的晚期非小细胞肺癌患者预后的预测价值

摘要/Abstract

摘要：

目的探讨一线接受免疫联合化疗的非小细胞肺癌（NSCLC）患者外周血炎症标志物治疗前后的变化趋势与疗效的相关性及对预后的预测价值。方法回顾性分析2018年10月至2023年5月就诊于武汉大学中南医院肺部肿瘤放化疗科的NSCLC患者的临床资料。采用χ²检验分析外周血炎症标志物的变化趋势与免疫联合化疗疗效之间的关系。使用二分类logistic回归评估客观缓解率（ORR）的影响因素。采用Kaplan-Meier曲线和Cox比例风险模型评价外周血炎症标志物的变化趋势对患者预后的预测价值。结果本研究共纳入102例接受一线免疫联合化疗的NSCLC患者。淋巴细胞与单核细胞比值（LMR）下降组（n=50）的骨转移患者比例比上升组（n=52）更高（χ²=4.28，P=0.039）;与上升组（n=51）患者相比，血小板与淋巴细胞比值（PLR）下降组（n=51）患者的病理类型以鳞状细胞癌多见（χ²=18.99，P<0.001）;预后营养指数（PNI）下降组（n=46）的女性患者比例比上升组（n=56）更高（χ²=4.29，P=0.038），差异均具有统计学意义。LMR上升组和下降组患者的2周期客观缓解率（ORR）分别为63.5%（33/52）和44.0%（22/50）（χ²=3.89，P=0.049），中性粒细胞与淋巴细胞比值（NLR）上升组（n=24）和下降组（n=78）患者的2周期ORR分别为29.2%（7/24）和61.5%（48/78）（χ²=7.74，P=0.005），系统免疫炎症指数（SII）上升组（n=27）和下降组（n=75）患者的2周期ORR分别为33.3%（9/27）和61.3%（46/75）（χ²=6.26，P=0.012），差异均具有统计学意义。多因素分析显示，外周血炎症标志物的变化趋势均与患者ORR无关。Kaplan-Meier生存曲线显示，SII下降组患者的中位无进展生存期（PFS）（未达到比7.1个月，χ²=9.35，P=0.002）和中位总生存期（OS）（未达到比16.6个月，χ²=11.08，P<0.001）均长于SII上升组，NLR下降组患者的中位OS比NLR上升组更长（未达到比22.2个月，χ²=4.56，P=0.033）。单因素分析显示，同时伴有脑、骨转移（HR=4.04，95%CI为1.23~13.35，P=0.022），SII上升（HR=2.83，95%CI为1.41~5.66，P=0.003）是NSCLC患者PFS的影响因素，同时伴有脑、骨转移（HR=3.47，95%CI为1.05~11.45，P=0.041），NLR上升（HR=2.17，95%CI为1.05~4.51，P=0.037）和SII上升（HR=3.12，95%CI为1.54~6.30，P=0.002）是NSCLC患者OS的影响因素。多因素分析结果显示，同时伴有脑、骨转移（HR=4.32，95%CI为1.30~14.40，P=0.017）和SII上升（HR=2.89，95%CI为1.44~5.81，P=0.003）均是NSCLC患者PFS的独立危险因素，同时伴有脑、骨转移（HR=3.76，95%CI为1.13~12.50，P=0.031）和SII上升（HR=3.47，95%CI为1.28~9.41，P=0.014）是NSCLC患者OS的独立危险因素。结论NSCLC患者外周血炎症标志物的变化趋势不能独立预测2周期免疫联合化疗的疗效。同时脑、骨转移和SII的变化趋势可作为预测一线接受免疫联合化疗治疗的晚期NSCLC患者PFS、OS的重要指标。同时发生脑、骨转移和SII上升提示NSCLC患者预后较差。

关键词:癌,非小细胞肺,免疫疗法,预后,炎症标志物,生存分析

Abstract:

ObjectiveTo investigate the correlation between pre- and post-treatment changing trends in peripheral blood inflammatory markers and efficacy and their predictive value for prognosis in non-small cell lung cancer （NSCLC） patients treated with the first-line immunotherapy plus chemotherapy.MethodsThe clinical data of NSCLC patients admitted to the Department of Radiation and Chemotherapy for Lung Oncology， Zhongnan Hospital of Wuhan University from October 2018 to May 2023 were retrospectively analyzed. Theχ²test was used to analyze the correlation between the changing trend of peripheral blood inflammatory markers and the efficacy of immunotherapy plus chemotherapy. The influencing factors of objective response rate （ORR） were assessed using binary logistic regression analysis. Kaplan-Meier survival curve and Cox proportional hazards model were used to analyze the prognostic value of the changing trend of peripheral blood inflammation markers on patients' prognosis.ResultsA total of 102 NSCLC patients treated with first-line immunotherapy plus chemotherapy were included. The proportion of patients with bone metastases was higher in the lymphocyte to monocyte ratio （LMR） decreased group （n=50） than that in the increased group （n=52）（χ²=4.28，P=0.039）， whereas the pathological type of patients in the platelet to lymphocyte ratio （PLR） decreased group （n=51） was more common in squamous carcinoma compared to patients in the increased group （n=51）（χ²=18.99，P<0.001）， and a higher proportion of patients in the prognostic nutritional index （PNI） decreased group （n=46） was female than that in the increased group （n=56）（χ²=4.29，P=0.038）， with statistically significant differences. The 2-cycle objective response rate （ORR） of patients in the LMR increased and decreased groups was 63.5% （33/52） and 44.0% （22/50）（χ²=3.89，P=0.049）， the 2-cycle ORR of patients in the neutrophil to lymphocyte ratio （NLR） increased （n=24） and decreased （n=78） groups was 29.2% （7/24） and 61.5% （48/78）（χ²=7.74，P=0.005）， and the 2-cycle ORR for patients in the systemic immune inflammatory index （SII） increased group （n=27） and decreased group （n=75） was 33.3% （9/27） and 61.3% （46/75）（χ²=6.26，P=0.012）， with statistically significant differences. Multivariate analysis showed that the changing trend of inflammatory markers in peripheral blood were not related to ORR. The Kaplan-Meier survival curve indicated that patients in the group with SII decreased had longer median progression-free survival （PFS）（not reachedvs.7.1 months，χ²=9.35，P=0.002） and median overall survival （OS）（not reachedvs.16.6 months，χ²=11.08，P<0.001） than those in the SII increased group， and patients in the NLR decreased group had longer median OS （not reachedvs.22.2 months，χ²=4.56，P=0.033） than that in the NLR increased group. Univariate analysis suggested that both brain and bone metastasis （HR=4.04， 95%CI： 1.23-13.35，P=0.022）， increased SII （HR=2.83， 95%CI： 1.41-5.66，P=0.003） were found to be significant factors affecting the PFS of NSCLC patients， both brain and bone metastasis （HR=3.47， 95%CI： 1.05-11.45，P=0.041）， increased NLR （HR=2.17， 95%CI： 1.05-4.51，P=0.037） and increased SII （HR=3.12， 95%CI： 1.54-6.30，P=0.002） were found to be significant factors affecting the OS of NSCLC patients. Multivariate analysis demonstrated that both brain and bone metastasis （HR=4.32， 95%CI： 1.30-14.40，P=0.017） and increased SII （HR=2.89， 95%CI： 1.44-5.81，P=0.003） were independent risk factors for PFS in NSCLC patients， both brain and bone metastasis （HR=3.76， 95%CI： 1.13-12.50，P=0.031） and increased SII （HR=3.47， 95%CI： 1.28-9.41，P=0.014） remained independent risk factors for OS in patients with NSCLC.ConclusionThe changing trend of peripheral blood inflammatory markers of NSCLC patients cannot independently predict the efficacy of 2-cycle immunotherapy plus chemotherapy. Both brain and bone metastasis， as well as the changing trend of SII can be used as important indicators to predict PFS and OS in advanced NSCLC patients treated with first-line immunotherapy plus chemotherapy. The simultaneous occurrence of brain and bone metastasis and SII increased suggest poor prognosis of NSCLC patients.

Key words:Carcinoma,non-small-cell lung,Immunotherapy,Prognosis,Inflammatory markers,Survival analysis

范志鹏, 余静, 胡静, 廖正凯, 徐禹, 欧阳雯, 谢丛华. 炎症标志物的变化趋势对一线接受免疫联合化疗的晚期非小细胞肺癌患者预后的预测价值[J]. 国际肿瘤学杂志, 2024, 51(5): 257-266.

Fan Zhipeng, Yu Jing, Hu Jing, Liao Zhengkai, Xu Yu, Ouyang Wen, Xie Conghua. Predictive value of changes in inflammatory markers for prognosis in patients with advanced non-small cell lung cancer treated with the first-line immunotherapy plus chemotherapy[J]. Journal of International Oncology, 2024, 51(5): 257-266.

图/表6

表1

外周血炎症标志物变化趋势与NSCLC患者临床基线特征的关系（例）"

基线特征	例数	MPV				LMR				NLR
基线特征	例数	上升组（n=25）	下降组（n=77）	χ²值	P值	上升组（n=52）	下降组（n=50）	χ²值	P值	上升组（n=24）	下降组（n=78）	χ²值	P值
年龄（岁）
<65	54	15	39	0.66	0.416	27	27	0.04	0.834	11	43	0.64	0.425
≥65	48	10	38	0.66	0.416	25	23	0.04	0.834	13	35	0.64	0.425
性别
男	86	19	67	1.00	0.318	45	41	0.40	0.529	21	65	0.03	0.865
女	16	6	10	1.00	0.318	7	9	0.40	0.529	3	13	0.03	0.865
病理类型
鳞状细胞癌	52	15	37	1.08	0.299	28	24	0.35	0.555	12	40	0.01	0.913
非鳞状细胞癌	50	10	40	1.08	0.299	24	26	0.35	0.555	12	38	0.01	0.913
TNM分期
ⅢB~ⅢC	27	8	19	0.52	0.471	15	12	0.31	0.579	8	19	0.76	0.384
Ⅳ	75	17	58	0.52	0.471	37	38	0.31	0.579	16	59	0.76	0.384
脑转移
是	11	3	8	<0.01	>0.999	6	5	0.06	0.802	1	10	0.67	0.413
否	91	22	69	<0.01	>0.999	46	45	0.06	0.802	23	68	0.67	0.413
骨转移
是	31	8	23	0.04	0.841	11	20	4.28	0.039	11	20	3.54	0.060
否	71	17	54	0.04	0.841	41	30	4.28	0.039	13	58	3.54	0.060
同时脑、骨转移
是	4	0	4	-	0.570	1	3	0.30	0.582	1	3	-	>0.999
否	98	25	73	-	0.570	51	47	0.30	0.582	23	75	-	>0.999
基线特征	例数	PLR				SII				PNI
基线特征	例数	上升组（n=51）	下降组（n=51）	χ²值	P值	上升组（n=27）	下降组（n=75）	χ²值	P值	上升组（n=56）	下降组（n=46）	χ²值	P值
年龄（岁）
<65	54	29	25	0.63	0.427	13	41	0.34	0.561	28	26	0.43	0.511
≥65	48	22	26	0.63	0.427	14	34	0.34	0.561	28	20	0.43	0.511
性别
男	86	42	44	0.30	0.586	23	63	<0.01	>0.999	51	35	4.29	0.038
女	16	9	7	0.30	0.586	4	12	<0.01	>0.999	5	11	4.29	0.038
病理类型
鳞状细胞癌	52	15	37	18.99	<0.001	11	41	1.54	0.215	31	21	0.95	0.329
非鳞状细胞癌	50	36	14	18.99	<0.001	16	34	1.54	0.215	25	25	0.95	0.329
TNM分期
ⅢB~ⅢC	27	12	15	0.45	0.501	9	18	0.89	0.346	17	10	0.96	0.326
Ⅳ	75	39	36	0.45	0.501	18	57	0.89	0.346	39	36	0.96	0.326
脑转移
是	11	6	5	0.10	0.750	2	9	0.09	0.766	6	5	<0.01	>0.999
否	91	45	46	0.10	0.750	25	66	0.09	0.766	50	41	<0.01	>0.999
骨转移
是	31	17	14	0.42	0.518	9	22	0.15	0.698	16	15	0.20	0.659
否	71	34	37	0.42	0.518	18	53	0.15	0.698	40	31	0.20	0.659
同时脑、骨转移
是	4	2	2	<0.01	>0.999	1	3	<0.01	>0.999	3	1	0.10	0.755
否	98	49	49	<0.01	>0.999	26	72	<0.01	>0.999	53	45	0.10	0.755

表1

表2

102例接受2周期免疫联合化疗晚期NSCLC患者ORR的logistic回归分析"

因素	单因素分析			多因素分析
因素	OR值	95%CI	P值	OR值	95%CI	P值
年龄（< 65岁/ ≥ 65岁）	0.98	0.45~2.14	0.963	-	-	-
性别（男/女）	0.66	0.22~1.97	0.455	-	-	-
病理类型（鳞状细胞癌/非鳞状细胞癌）	2.21	1.00~4.89	0.050	-	-	-
TNM分期（Ⅳ/ⅢB~ⅢC）	1.12	0.46~2.70	0.801	-	-	-
脑转移（有/无）	1.03	0.29~3.61	0.965	-	-	-
骨转移（有/无）	0.60	0.26~1.41	0.243	-	-	-
同时脑、骨转移（有/无）	0.27	0.03~2.70	0.266	-	-	-
MPV变化（上升/下降）	1.12	0.45~2.77	0.810	-	-	-
LMR变化（上升/下降）	2.21	1.00~4.89	0.050	-	-	-
NLR变化（上升/下降）	0.26	0.10~0.69	0.007	0.37	0.10~1.43	0.149
PLR变化（上升/下降）	0.49	0.22~1.08	0.075	-	-	-
SII变化（上升/下降）	0.32	0.13~0.80	0.014	0.61	0.17~2.18	0.445
PNI变化（上升/下降）	1.57	0.77~3.44	0.264	-	-	-

表2

图1

图2

表3

102例接受免疫联合化疗晚期NSCLC患者PFS的Cox回归分析"

因素	单因素分析			多因素分析
因素	HR值	95%CI	P值	HR值	95%CI	P值
年龄（< 65岁/ ≥ 65岁）	1.58	0.78~3.19	0.203	-	-	-
性别（男/女）	1.14	0.40~3.25	0.804	-	-	-
病理类型（鳞状细胞癌/非鳞状细胞癌）	1.46	0.73~2.92	0.282	-	-	-
TNM分期（Ⅳ/ⅢB~ⅢC）	0.87	0.42~1.84	0.719	-	-	-
放疗（有/无）	2.00	0.93~4.30	0.078	-	-	-
脑转移（有/无）	1.35	0.47~3.83	0.578	-	-	-
骨转移（有/无）	1.25	0.61~2.58	0.549	-	-	-
同时脑、骨转移（有/无）	4.04	1.23~13.35	0.022	4.32	1.30~14.40	0.017
MPV变化（上升/下降）	1.03	0.46~2.28	0.947	-	-	-
LMR变化（上升/下降）	0.61	0.30~1.21	0.157	-	-	-
NLR变化（上升/下降）	2.02	0.98~4.18	0.057	-	-	-
PLR变化（上升/下降）	1.51	0.76~3.01	0.245	-	-	-
SII变化（上升/下降）	2.83	1.41~5.66	0.003	2.89	1.44~5.81	0.003
PNI变化（上升/下降）	0.60	0.30~1.18	0.139	-	-	-

表3

表4

102例接受免疫联合化疗晚期NSCLC患者OS的Cox回归分析"

因素	单因素分析			多因素分析
因素	HR值	95%CI	P值	HR值	95%CI	P值
年龄（< 65岁/ ≥ 65岁）	1.44	0.71~2.90	0.308	-	-	-
性别（男/女）	1.16	0.41~3.31	0.776	-	-	-
病理类型（鳞状细胞癌/非鳞状细胞癌）	1.40	0.70~2.79	0.344	-	-	-
TNM分期（Ⅳ/ⅢB~ⅢC）	0.92	0.44~1.93	0.816	-	-	-
放疗（有/无）	1.42	0.66~3.07	0.372	-	-	-
脑转移（有/无）	1.14	0.40~3.24	0.808	-	-	-
骨转移（有/无）	1.15	0.56~2.37	0.708	-	-	-
同时脑、骨转移（有/无）	3.47	1.05~11.45	0.041	3.76	1.13~12.50	0.031
MPV变化（上升/下降）	1.03	0.46~2.28	0.952	-	-	-
LMR变化（上升/下降）	0.58	0.29~1.16	0.126	-	-	-
NLR变化（上升/下降）	2.17	1.05~4.51	0.037	0.89	0.32~2.49	0.816
PLR变化（上升/下降）	1.78	0.88~3.56	0.106	-	-	-
SII变化（上升/下降）	3.12	1.54~6.30	0.002	3.47	1.28~9.41	0.014
PNI变化（上升/下降）	0.58	0.29~1.16	0.123	-	-	-

表4

参考文献36

[1]	Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023[J].CA Cancer J Clin,2023,73(1): 17-48. DOI:10.3322/caac.21763.
[2]	Lu XJ, Wan JY, Shi HQ. Platelet-to-lymphocyte and neutrophil-to-lymphocyte ratios are associated with the efficacy of immunotherapy in stage Ⅲ/Ⅳ non-small cell lung cancer[J].Oncol Lett,2022,24(2): 266. DOI:10.3892/ol.2022.13386.
[3]	Miller KD, Nogueira L, Devasia T, et al. Cancer treatment and survivorship statistics, 2022[J].CA Cancer J Clin,2022,72(5): 409-436. DOI:10.3322/caac.21731.
[4]	Tang J, Hubbard-Lucey VM, Pearce L, et al. The global landscape of cancer cell therapy[J].Nat Rev Drug Discov,2018,17(7): 465-466. DOI:10.1038/nrd.2018.74. pmid:29795477
[5]	Thompson JA. New NCCN guidelines: recognition and management of immunotherapy-related toxicity[J].J Natl Compr Canc Netw,2018,16(5s): 594-596. DOI:10.6004/jnccn.2018.0047.
[6]	Yang Y, Yu YF, Lu S. Effectiveness of PD-1/PD-L1 inhibitors in the treatment of lung cancer: brightness and challenge[J].Sci China Life Sci,2020,63(10): 1499-1514. DOI:10.1007/s11427-019-1622-5.
[7]	Doroshow DB, Sanmamed MF, Hastings K, et al. Immunotherapy in non-small cell lung cancer: facts and hopes[J].Clin Cancer Res,2019,25(15): 4592-4602. DOI:10.1158/1078-0432.Ccr-18-1538. pmid:30824587
[8]	Reck M, Remon J, Hellmann MD. First-line immunotherapy for non-small-cell lung cancer[J].J Clin Oncol,2022,40(6): 586-597. DOI:10.1200/jco.21.01497. pmid:34985920
[9]	Diem S, Schmid S, Krapf M, et al. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as prognostic markers in patients with non-small cell lung cancer (NSCLC) treated with nivolumab[J].Lung Cancer,2017,111: 176-181. DOI:10.1016/j.lungcan.2017.07.024. pmid:28838390
[10]	Jin J, Yang L, Liu D, et al. Prognostic value of pretreatment lymphocyte-to-monocyte ratio in lung cancer: a systematic review and meta-analysis[J].Technol Cancer Res Treat,2021,20: 1533033820983085. DOI:10.1177/1533033820983085.
[11]	Peng L, Wang Y, Liu F, et al. Peripheral blood markers predictive of outcome and immune-related adverse events in advanced non-small cell lung cancer treated with PD-1 inhibitors[J].Cancer Immunol Immunother,2020,69(9): 1813-1822. DOI:10.1007/s00262-020-02585-w. pmid:32350592
[12]	Sakin A, Secmeler S, Arici S, et al. Prognostic significance of mean platelet volume on local advanced non-small cell lung cancer managed with chemoradiotherapy[J].Sci Rep,2019,9(1): 3959. DOI:10.1038/s41598-019-40589-4. pmid:30850724
[13]	Zheng L, Xiong A, Wang S, et al. Decreased monocyte-to-lymphocyte ratio was associated with satisfied outcomes of first-line PD-1 inhibitors plus chemotherapy in stage ⅢB -Ⅳ non-small cell lung cancer[J].Front Immunol,2023,14: 1094378. DOI:10.3389/fimmu.2023.1094378.
[14]	Lim JU, Kang HS, Yeo CD, et al. Predictability of early changes in derived neutrophil-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio in patients with advanced non-small cell lung cancer treated with immune checkpoint inhibitors[J].J Thorac Dis,2021,13(5): 2824-2832. DOI:10.21037/jtd-20-3416. pmid:34164174
[15]	Ksienski D, Wai ES, Alex D, et al. Prognostic significance of the neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio for advanced non-small cell lung cancer patients with high PD-L1 tumor expression receiving pembrolizumab[J].Transl Lung Cancer Res,2021,10(1): 355-367. DOI:10.21037/tlcr-20-541.
[16]	Huai QL, Luo CY, Song P, et al. Peripheral blood inflammatory biomarkers dynamics reflect treatment response and predict prognosis in non-small cell lung cancer patients with neoadjuvant immunotherapy[J].Cancer Sci,2023,114(12): 4484-4498. DOI:10.1111/cas.15964.
[17]	Li M, Zhao S, Lopez G, et al. Mean platelet volume, thrombocytosis, and survival in non-small cell lung cancer patients treated with first-line pembrolizumab alone or with chemotherapy[J].Cancer Immunol Immunother,2023,72(7): 2067-2074. DOI:10.1007/s00262-023-03392-9.
[18]	Sekine K, Kanda S, Goto Y, et al. Change in the lymphocyte-to-monocyte ratio is an early surrogate marker of the efficacy of nivolumab monotherapy in advanced non-small-cell lung cancer[J].Lung Cancer,2018,124: 179-188. DOI:10.1016/j.lungcan. 2018.08.012. pmid:30268458
[19]	Li Y, Zhang Z, Hu Y, et al. Pretreatment neutrophil-to-lymphocyte ratio (NLR) may predict the outcomes of advanced non-small-cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs)[J].Front Oncol,2020,10: 654. DOI:10.3389/fonc.2020.00654. pmid:32656072
[20]	Yan X, Wang J, Mao J, et al. Identification of prognostic nutritional index as a reliable prognostic indicator for advanced lung cancer patients receiving immune checkpoint inhibitors[J].Front Nutr,2023,10: 1213255. DOI:10.3389/fnut.2023.1213255.
[21]	Zhang N, Jiang J, Tang S, et al. Predictive value of neutrophil-lymphocyte ratio and platelet-lymphocyte ratio in non-small cell lung cancer patients treated with immune checkpoint inhibitors: a meta-analysis[J].Int Immunopharmacol,2020,85: 106677. DOI:10.1016/j.intimp.2020.106677.
[22]	Liu N, Mao J, Tao P, et al. The relationship between NLR/PLR/LMR levels and survival prognosis in patients with non-small cell lung carcinoma treated with immune checkpoint inhibitors[J].Medicine (Baltimore),2022,101(3): e28617. DOI:10.1097/MD.0000000000028617.
[23]	Coussens LM, Werb Z. Inflammation and cancer[J].Nature,2002,420(6917): 860-867. DOI:10.1038/nature01322.
[24]	Fan R, Chen Y, Xu G, et al. Combined systemic immune-inflam-matory index and prognostic nutritional index predict outcomes in advanced non-small cell lung cancer patients receiving platinum-doublet chemotherapy[J].Front Oncol,2023,13: 996312. DOI:10.3389/fonc.2023.996312.
[25]	Schlesinger M. Role of platelets and platelet receptors in cancer metastasis[J].J Hematol Oncol,2018,11(1): 125. DOI:10. 1186/s13045-018-0669-2.
[26]	Watanabe K, Noma D, Masuda H, et al. Preoperative inflammation-based scores predict early recurrence after lung cancer resection[J].J Thorac Dis,2021: 2812-2823. DOI:10.21037/jtd-20-3458.
[27]	Scilla KA, Bentzen SM, Lam VK, et al. Neutrophil-lymphocyte ratio is a prognostic marker in patients with locally advanced (stage ⅢA and ⅢB) non-small cell lung cancer treated with combined modality therapy[J].Oncologist,2017,22(6): 737-742. DOI:10.1634/theoncologist.2016-0443.
[28]	Putzu C, Cortinovis DL, Colonese F, et al. Blood cell count indexes as predictors of outcomes in advanced non-small-cell lung cancer patients treated with nivolumab[J].Cancer Immunol Immunother,2018,67(9): 1349-1353. DOI:10.1007/s00262-018-2182-4. pmid:29947960
[29]	Zhang YP, Zhang R, Zhu HY, et al. Circulating low absolute CD4⁺T cell counts may predict poor prognosis in extranodal NK/T-cell lymphoma patients treating with pegaspargase-based chemotherapy[J].Cancer Res Treat,2019,51(1): 368-377. DOI:10.4143/crt.2018.010.
[30]	Gooden MJM, de Bock GH, Leffers N, et al. The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis[J].Br J Cancer,2011,105(1): 93-103. DOI:10.1038/bjc.2011.189.
[31]	Rosenberg SA. Progress in human tumour immunology and immunotherapy[J].Nature,2001,411(6835): 380-384. DOI:10.1038/ 35077246.
[32]	Li CW, Wu JQ, Jiang L, et al. The predictive value of inflammatory biomarkers for major pathological response in non-small cell lung cancer patients receiving neoadjuvant chemoimmunotherapy and its association with the immune-related tumor microenvironment: a multi-center study[J].Cancer Immunol Immunother,2023,72(3): 783-794. DOI:10.1007/s00262-022-03262-w.
[33]	Chu X, Niu L, Xiao G, et al. The long-term and short-term efficacy of immunotherapy in non-small cell lung cancer patients with brain metastases: a systematic review and meta-analysis[J].Front Immunol,2022,13: 875488. DOI:10.3389/fimmu.2022. 875488.
[34]	Wakuda K, Yabe M, Kodama H, et al. Efficacy of pembrolizumab in patients with brain metastasis caused by previously untreated non-small cell lung cancer with high tumor PD-L1 expression[J].Lung Cancer,2021,151: 60-68. DOI:10.1016/j.lungcan.2020. 11.009. pmid:33246646
[35]	Asano YH, Yamamoto N, Demura S, et al. Novel predictors of immune checkpoint inhibitor response and prognosis in advanced non-small-cell lung cancer with bone metastasis[J].Cancer Med,2023,12(11): 12425-12437. DOI:10.1002/cam4.5952.
[36]	Liu L, Shi Z, Qiu X. Impact of bone metastasis on the prognosis of non-small cell lung cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis[J].Clin Transl Oncol,2024,26(3): 747-755. DOI:10.1007/s12094-023-03300-8.