PD-1、PD-L1在铂耐药卵巢上皮性癌组织中的表达及其临床意义

翟欣影; 王丽华; 李艳华

doi:10.16766/j.cnki.issn.1674-4152.003545

PD-1、PD-L1在铂耐药卵巢上皮性癌组织中的表达及其临床意义

doi: 10.16766/j.cnki.issn.1674-4152.003545

蚌埠医科大学第一附属医院肿瘤妇科，安徽蚌埠 233004

基金项目:

安徽高校自然科学研究项目 KJ2021A0720

详细信息

通讯作者:
李艳华，E-mail：bblyh1964@126.com

中图分类号: R737.31 R730.43
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- 文章访问数: 40
- HTML全文浏览量: 31
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- 被引次数: 0
出版历程
- 收稿日期: 2023-08-14
- 网络出版日期: 2024-07-22

Expression of PD-1 and PD-L1 in platinum-resistant ovarian epithelial carcinoma and their clinical significance

Department of Gynaecologic Oncology, the First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, China

摘要

摘要: 目的探讨程序性死亡受体1(PD-1)、程序性死亡受体配体1(PD-L1)在铂耐药卵巢上皮性癌患者组织中的表达情况, 分析铂耐药卵巢上皮性癌患者PD-1、PD-L1表达与临床特征及预后的关系。方法收集2018年1月—2021年6月于蚌埠医科大学第一附属医院接受手术治疗的111例卵巢癌患者组织蜡块(71例铂耐药组蜡块和40例铂敏感组蜡块)，另取10例卵巢良性组织蜡块作为对照。采用ELiVision ^TM免疫组化法检测样本中PD-1、PD-L1表达水平，分析两者表达与患者病理特征和预后的关系。结果 PD-1、PD-L1在铂敏感组和铂耐药组阳性率分别为22.5%、32.5%和42.3%、53.5%，铂耐药组中PD-1、PD-L1阳性率高于铂敏感组(P＜0.05)；PD-1、PD-L1在浆液性癌和非浆液性癌组织中阳性表达率分别为50.0%、61.5%和21.1%、31.6%，PD-1、PD-L1在手术病理分期Ⅲ~Ⅳ期和Ⅰ~Ⅱ期患者中阳性表达率分别为51.0%、63.3%和22.7%、31.8%，非浆液性、Ⅰ~Ⅱ期患者PD-1、PD-L1表达低于浆液性癌和Ⅲ~Ⅳ期患者(P＜0.05)；多因素Cox比例风险模型结果显示，PD-1阳性(HR=3.905，P=0.001)、PD-L1阳性(HR=4.581, P=0.002)、手术病理分期为Ⅲ~Ⅳ期(HR=3.948，P=0.026)是铂耐药卵巢上皮性癌患者预后的独立危险因素；生存分析显示PD-1、PD-L1阳性患者两年累积生存率明显低于其他表达情况(P＜0.05)。结论卵巢上皮性癌组织中PD-1、PD-L1高表达与耐药有关，从而导致肿瘤的恶性进展和生存时间的缩短，是患者预后不良的标志之一。
- 上皮性卵巢癌 /
- 程序性死亡受体－配体1 /
- 铂耐药 /
- 化疗耐药 /
- 免疫治疗 /
- 程序性死亡受体1
Abstract: Objective To investigate the expression of programmed death receptor 1 (PD-1) and programmed death receptor-ligand 1 (PD-L1) in the tissues of patients with platinum-resistant ovarian epithelial cancer, and to analyze the relationship between the expression of PD-1 and PD-L1 in patients with platinum-resistant ovarian epithelial cancer and clinical characteristics and prognosis. Methods The tissue paraffin blocks of 111 patients with ovarian cancer (71 cases of platinum-resistant tissue paraffin blocks and 40 cases of platinum-sensitive tissue paraffin blocks) who underwent surgical treatment in the First Affiliated Hospital of Bengbu Medical University from January 2018 to June 2021 were collected, and 10 cases of benign ovarian tissue paraffin blocks were taken as controls. The expression levels of PD-1 and PD-L1 in ovarian cancer tissues were detected by ELiVision^TM immunohistochemistry method, and the relationships between the expression levels and pathological features and prognosis were analyzed. Results The positive rates of PD-1 and PD-L1 in the platinum-sensitive group and platinum-resistant group were 22.5%, 32.5% and 42.3%, 53.5%, respectively. The positive rates of PD-1 and PD-L1 in the drug-resistant group were higher than those in the platinum-sensitive group (P < 0.05). The positive expression rates of PD-1 and PD-L1 in serous and non-serous cancer tissues were 50.0%, 61.5% and 21.1%, 31.6%, respectively. The positive expression rates of PD-1 and PD-L1 in surgical pathological stage Ⅲ-Ⅳ and Ⅰ-Ⅱ were 51.0%, 63.3 %, and 22.7%, 31.8%, respectively. The expressions of PD-1 and PD-L1 were significantly lower than those in serous carcinoma and stage Ⅲ to Ⅳ patients, with statistical significance (P < 0.05). The multifactorial Cox proportional risk model shows: PD-1 positive group (HR=3.905, P=0.001), PD-L1 positive group (HR=4.581, P=0.002), surgical pathological stage Ⅲ and Ⅳ stages (HR=3.948, P=0.026) were independent risk prognostic factors affecting survival of patients with platinum-resistant ovarian epithelial cancer. Survival analysis showed that the two-year survival rate of PD-1 and PD-L1 positive patients were lower than that of negative patients (P < 0.05). Conclusion The high expression of PD-1 and PD-L1 in ovarian epithelial carcinoma tissues is related to drug resistance, which leads to malignant progression of tumor and shortened survival time, and is one of the indicators of poor prognosis of patients.
- Epithelial ovarian cancer /
- Programmed death receptor-ligand 1 /
- Platinum resistance /
- Chemotherapy resistance /
- Immunotherapy /
- Programmed death receptor 1

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图 1 PD-1和PD-L1在卵巢癌组织及卵巢良性组织中的表达(EnVision^TM免疫组化法, ×200)

Figure 1. Expression of PD-1 and PD-L1 in ovarian cancer tissues and benign ovarian tissues (EnVisionTM immunohistochemistry, ×200)

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图 2 PD-1表达情况对铂耐药卵巢上皮性癌患者预后的影响

Figure 2. Effect of expression of PD-1 on prognosis of patients with platinum-resistant epithelial ovarian cancer

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图 3 PD-L1表达情况对铂耐药卵巢上皮性癌患者预后的影响

Figure 3. Effect of expression of PD-L1 on prognosis of patients with platinum-resistant epithelial ovarian cancer

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图 4 PD-1联合PD-L1表达情况对铂耐药卵巢上皮性癌患者预后的影响

Figure 4. Effect of expression of PD-1 combined with PD-L1 on prognosis of patients with platinum-resistant epithelial ovarian cancer

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表 1 2组卵巢上皮性癌患者PD-1、PD-L1阳性率比较[例(%)]

Table 1. Comparison of the positive rates of PD-1 and PD-L1 in two groups of ovarian epithelial carcinoma patients[cases (%)]

组别	例数	PD-1		PD-L1
组别	例数	阴性	阳性	阴性	阳性
铂敏感组	40	31(77.5)	9(22.5)	27(67.5)	13(32.5)
铂耐药组	71	41(57.7)	30(42.3)	33(46.5)	38(53.5)
χ²值		4.318		4.552
P值		0.036		0.033

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表 2 不同临床病理特征铂耐药卵巢上皮性癌患者PD-1、PD-L1表达情况比较[例(%)]

Table 2. Comparison of expression of PD-1 and PD-L1 in patients with platinum-resistant epithelial ovarian cancer with different clinicopathological features[cases (%)]

临床资料	例数	PD-1		χ²值	P值	PD-L1		χ²值	P值
临床资料	例数	阴性	阳性	χ²值	P值	阴性	阳性	χ²值	P值
年龄				2.427	0.119			0.244	0.621
＜55岁	43	28(65.1)	15(34.9)			21(48.8)	22(51.2)
≥55岁	28	13(46.4)	15(53.6)			12(42.9)	16(57.1)
病理类型				4.779	0.029			5.021	0.025
非浆液性	19	15(78.9)	4(21.1)			13(68.4)	6(31.6)
浆液性	52	26(50.0)	26(50.0)			20(38.5)	32(61.5)
腹水				0.053	0.817			0.174	0.676
无	32	18(56.3)	14(43.7)			14(43.7)	18(56.3)
有	39	23(59.0)	16(41.0)			19(48.7)	20(51.3)
FIGO分期				4.981	0.026			6.036	0.014
Ⅰ~Ⅱ	22	17(77.3)	5(22.7)			15(68.2)	7(31.8)
Ⅲ~Ⅳ	49	24(49.0)	25(51.0)			18(36.7)	31(63.3)
原发部位				0.352	0.553			2.071	0.150
单侧	21	11(52.4)	10(47.6)			7(33.3)	14(66.7)
双侧	50	30(60.0)	20(40.0)			26(52.0)	24(48.0)
绝经状态				0.099	0.753			0.001	0.979
否	13	7(53.8)	6(46.2)			6(46.2)	7(53.8)
是	58	34(58.6)	24(41.4)			27(46.6)	31(53.4)

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表 3 铂耐药卵巢上皮性癌患者预后影响因素的单因素Cox回归分析

Table 3. Univariate Cox regression analysis of prognostic factors in patients with platinum-resistant epithelial ovarian cancer

变量	B	SE	Waldχ²	P值	HR(95% CI)
年龄≥55岁	0.343	0.357	0.925	0.336	1.409(0.700~2.836)
病理类型为浆液性	1.173	0.535	4.811	0.028	3.233(1.133~9.224)
腹水	0.131	0.357	0.134	0.715	1.139(0.566~2.293)
FIGO分期为Ⅲ~Ⅳ期	1.849	0.611	9.157	0.002	6.351(1.918~21.032)
原发部位为双侧	-0.412	0.373	1.219	0.270	0.662(0.319~1.376)
绝经	0.111	0.488	0.051	0.821	1.117(0.429~2.905)
PD-1阳性	1.552	0.385	16.245	＜0.001	4.722(2.220~10.045)
PD-L1阳性	1.756	0.458	14.684	＜0.001	5.791(2.359~14.220)
注：各变量赋值如下，年龄≥55岁=1，＜55岁=0；病理类型为浆液性=1，非浆液性=0；有腹水=1，无腹水=0；FIGO分期Ⅲ~Ⅳ期=1，Ⅰ~Ⅱ期=0，肿瘤原发部位为双侧=1，单侧=0；绝经=1，未绝经=0；PD-1，阳性=1，阴性=0；PD-L1，阳性=1，阴性=0。

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表 4 铂耐药卵巢上皮性癌患者预后影响因素的多因素Cox回归分析

Table 4. Multivariate Cox regression analysis of prognostic factors in patients with platinum-resistant epithelial ovarian cancer

变量	B	SE	Waldχ²	P值	HR(95% CI)
病理类型为浆液性	0.100	0.604	0.028	0.868	1.106(0.338~3.611)
FIGO分期为Ⅲ~Ⅳ期	1.373	0.617	4.947	0.026	3.948(1.177~13.243)
PD-1阳性	1.362	0.409	11.115	0.001	3.905(1.753~8.699)
PD-L1阳性	1.522	0.501	9.226	0.002	4.581(1.716~12.232)
注：各变量赋值如下，病理类型为非浆液性=1，浆液性=2；FIGO分期Ⅰ~Ⅱ期=1，Ⅲ~Ⅳ期=2；PD-1，阴性=0，阳性=1；PD-L1，阴性=0，阳性=1。

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表 5 不同PD-1、PD-L1表达情况铂耐药卵巢上皮性癌患者总生存率比较

Table 5. Comparison of overall survival rate of patients with platinum-resistant epithelial ovarian cancer with different expressions of PD-1 and PD-L1

项目	例数	总生存率(%)		log-rank χ²值	P值
项目	例数	1年	2年	log-rank χ²值	P值
PD-1				20.208	＜0.001
阴性	41	97.6	82.9
阳性	30	90.0	40.0
PD-L1				19.133	＜0.001
阴性	33	100.0	87.9
阳性	38	89.5	44.7
PD-1+PD-L1				37.356	＜0.001
双阴性	22	100.0	100.0
PD-1阳性+PD-L1阴性	11	100.0	63.6
PD-1阴性+PD-L1阳性	19	94.7	63.2
双阳性	19	84.2	26.3

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参考文献(21)

[1]	SUNG H, FERLAY J, SIEGEL R L, et al. Global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249. doi: 10.3322/caac.21660
[2]	HAVASI A, CAINAP S S, HAVASI A T, et al. Ovarian cancer-insights into platinum resistance and overcoming it[J]. Medicina Kaunas, 2023, 59(3): 544. DOI: 10.3390/medicina59030544.
[3]	TORRE L A, TRABERT B, DESANTIS C E, et al. Ovarian cancer statistics, 2018[J]. CA Cancer J Clin, 2018, 68(4): 284-296. doi: 10.3322/caac.21456
[4]	WALLIS B, BOWMAN K R, LU P, et al. The challenges and prospects of P53-based therapies in ovarian cancer[J]. Biomolecules, 2023, 13(1): 159. DOI: 10.3390/biom13010159.
[5]	PAWLOWSKA A, SKIBA W, SUSZCZYK D, et al. The dual blockade of the TIGIT and PD-1/PD-L1 pathway as a new hope for ovarian cancer patients[J]. Cancers(Basel), 2022, 14(23): 5757. DOI: 10.3390/cancers14235757.
[6]	WANG Y M, CAI W, XUE Q M, et al. Prognostic role of different PD-L1 expression patterns and tumor-infiltrating lymphocytes in high-grade serous ovarian cancer: a systematic review and meta-analysis[J]. Front Immunol, 2023, 14: 1234894. DOI: 10.3389/fimmu.2023.1234894.
[7]	闫风彩, 金木兰, 石峰, 等. PD-1/PD-L1在恶性肿瘤中的表达及研究进展[J]. 诊断病理学杂志, 2019, 26(1): 61-65. doi: 10.3969/j.issn.1007-8096.2019.01.018 YAN F C, JIN M L, SHI F, et al. Expression and research progress of PD-1/PD-L1 in malignant tumors[J]. Chinese Journal of Diagnostic Pathology, 2019, 26(1): 61-65. doi: 10.3969/j.issn.1007-8096.2019.01.018
[8]	WANG D R, WU X L, SUN Y L. Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response[J]. Signal Transduct Target Ther, 2022, 7(1): 331. DOI: 10.1038/s41392-022-01136-2.
[9]	高五岳, 郭园园, 刘贝贝, 等. 不同距离癌旁组织PD-1和PD-L1表达对肾部分切除术边距选择的临床意义[J]. 中华全科医学, 2019, 17(12): 2004-2007, 2034. doi: 10.16766/j.cnki.issn.1674-4152.001113 GAO W Y, GUO Y Y, LIU B B, et al. The clinical significance of PD-1 and PD-L1 expression in different distance paracancer tissues in selection of margin for partial nephrectomy[J]. Chinese Journal of General Practice, 2019, 17(12): 2004-2007, 2034. doi: 10.16766/j.cnki.issn.1674-4152.001113
[10]	鞠策, 高景春, 张朋新, 等. PD-1和PD-L1在卵巢上皮性癌组织中的表达及其意义[J]. 中华妇产科杂志, 2020, 55(8): 529-534. doi: 10.3760/cma.j.cn112141-20200301-00155 JU C, GAO J C, ZHANG P X, et al. Expression and significance of PD-1 and PD-L1 in ovarian epithelial carcinoma[J]. Chinese Journal of Obstetrics and Gynecology, 2020, 55(8): 529-534. doi: 10.3760/cma.j.cn112141-20200301-00155
[11]	彩琴. 上皮性卵巢癌患者的临床病理情况分析[J]. 实用妇科内分泌电子杂志, 2022, 9(11): 14-17. https://www.cnki.com.cn/Article/CJFDTOTAL-FKDZ202211004.htm CAI Q. Clinicopathological analysis of patients with epithelial ovarian cancer[J]. Electronic Journal of Gynecologic Endocrinology, 2022, 9(11): 14-17. https://www.cnki.com.cn/Article/CJFDTOTAL-FKDZ202211004.htm
[12]	赵玲军. 卵巢癌靶向治疗新进展[J]. 现代实用医学, 2019, 31(7): 854-857. doi: 10.3969/j.issn.1671-0800.2019.07.003 ZHAO L J. New progress of targeted therapy for ovarian cancer[J]. Modern Practical Medicine, 2019, 31(7): 854-857. doi: 10.3969/j.issn.1671-0800.2019.07.003
[13]	王丝雨, 王娜, 张兰, 等. PD-1和PD-L1在卵巢上皮性癌组织中的表达及其与免疫抑制相关因子的关联[J]. 实用癌症杂志, 2022, 37(7): 1076-1079. doi: 10.3969/j.issn.1001-5930.2022.07.007 WANG S Y, WANG N, ZHANG L, et al. Expression of PD-1 and PD-L1 in ovarian epithelial carcinoma and their association with immunosuppressive factors[J]. Journal of Practical Cancer, 2022, 37(7): 1076-1079. doi: 10.3969/j.issn.1001-5930.2022.07.007
[14]	陈洪丞成, 张宏权, 魏潇凡. PD-L1表达及其调控在肿瘤治疗中作用的研究进展[J]. 生理科学进展, 2023, 54(6): 526-532. https://www.cnki.com.cn/Article/CJFDTOTAL-SLKZ202306010.htm CHEN H C C, ZHANG H Q, WEI X F. Research progress of PD-L1 expression and its regulation in the treatment of tumor[J]. Advances in Physiological Sciences, 2023, 54(6): 526-532. https://www.cnki.com.cn/Article/CJFDTOTAL-SLKZ202306010.htm
[15]	毛若南, 姜伟. PD-1/PD-L1免疫抑制剂治疗卵巢癌的临床应用进展[J]. 国际妇产科学杂志, 2021, 48(6): 605-609. https://www.cnki.com.cn/Article/CJFDTOTAL-GWVC202106002.htm MAO R N, LIANG W. Clinical application progress of PD-1/PD-L1 immunosuppressive agents in the treatment of ovarian cancer[J]. International Journal of Obstetrics and Gynecology, 2021, 48(6): 605-609. https://www.cnki.com.cn/Article/CJFDTOTAL-GWVC202106002.htm
[16]	张智, 张一琼. Foxp3+Tregs及PD1在上皮性卵巢癌组织中的表达及其临床病理意义[J]. 南昌大学学报(医学版), 2018, 58(5): 54-58, 69. https://www.cnki.com.cn/Article/CJFDTOTAL-JXYB201805012.htm ZHANG Z, ZHANG Y Q. The expression and clinical pathological significance of Foxp3+Tregs and PD1 in epithelial ovarian cancer tissue[J]. Journal of Nanchang University (Medical Edition), 2018, 58(5): 54-58, 69. https://www.cnki.com.cn/Article/CJFDTOTAL-JXYB201805012.htm
[17]	袁风玲, 贾淑慧, 江源. 卵巢癌组织中PD-L1及PD-L2的表达及其预后判断价值[J]. 实用癌症杂志, 2020, 35(10): 1622-1624, 1638. doi: 10.3969/j.issn.1001-5930.2020.10.015 YUAN F L, JIA S H, JIANG Y. Expression and prognostic value of PD-L1 and PD-L2 in ovarian cancer tissue[J]. Journal of Practical Cancer, 2020, 35(10): 1622-1624, 1638. doi: 10.3969/j.issn.1001-5930.2020.10.015
[18]	WANG Y F, ZHU X H, Li C. Analysis of the relationship between LncRNA and PD-L1 expression and chemotherapy resistance in ovarian cancer patients[J]. 中国医学创新, 2022, 19(11): 169-173. doi: 10.3969/j.issn.1674-4985.2022.11.042
[19]	杨蓉, 张春莉. PD-1和PD-L1在卵巢癌中的研究进展[J]. 延安大学学报(医学科学版), 2019, 17(1): 94-96, 101. https://www.cnki.com.cn/Article/CJFDTOTAL-YAXY201901026.htm YANG R, ZHANG C L. Research progress of PD-1 and PD-L1 in ovarian cancer[J]. Journal of Yan'an University (Medical Science Edition), 2019, 17(1): 94-96, 101. https://www.cnki.com.cn/Article/CJFDTOTAL-YAXY201901026.htm
[20]	杜晓丽, 张东明, 徐洪. 卵巢癌组织中PD-1、PD-L1和Cyclin D1蛋白表达与预后的关系[J]. 分子诊断与治疗杂志, 2021, 13(10): 1680-1684. doi: 10.3969/j.issn.1674-6929.2021.10.032 DU X L, ZHANG D M, XU H. The relationship between PD-1, PD-L1, and Cyclin D1 protein expression and prognosis in ovarian cancer tissue[J]. Journal of Molecular Diagnosis and Treatment, 2021, 13(10): 1680-1684. doi: 10.3969/j.issn.1674-6929.2021.10.032
[21]	邓宇鹏, 许娜, 娄彤, 等. PD-L1在卵巢高级别浆液性癌预后中的价值[J]. 中国实验诊断学, 2020, 24(10): 1649-1653. doi: 10.3969/j.issn.1007-4287.2020.10.020 DENG Y P, XU N, LOU T, et al. The value of PD-L1 in the prognosis of advanced serous ovarian cancer[J]. Chinese Journal of Experimental Diagnosis, 2020, 24(10): 1649-1653. doi: 10.3969/j.issn.1007-4287.2020.10.020