Research Progress on Lymphocyte Activation Gene-3 in Gynecological Tumors

doi:10.12280/gjfckx.20240456

Abstract

Abstract:

Gynecological tumors are one of the important causes of death among women. Although standard treatments can improve the condition of some patients, many still experience disease progression and poor prognosis. Early diagnosis and treatment are crucial for improving the prognosis of gynecological tumors and reducing the burden of disease. Therefore, identifying more effective therapeutic targets is essential. Lymphocyte activation gene-3 (LAG-3) is an emerging immune checkpoint molecule that is highly expressed on the surface of tumor infiltrating lymphocytes in various types of tumors. It participates in immune suppression and tumor immune evasion by inhibiting the function of immune cells. Recent studies have shown that LAG-3 is highly expressed in gynecological tumors and is closely associated with tumor development, making it a promising new target for immunotherapy in gynecological tumors. This review outlines the structure and function of LAG-3 and discusses the research progress on its association with the three major gynecological tumors, providing new insights for future therapeutic research in gynecological tumors.

Key words: Genital neoplasms, female, Immune checkpoint inhibitors, Antineoplastic agents, Tumor microenvironment, Immunotherapy, Lymphocyte activation gene-3

BAI Yao-jun, HU Xiao-hong, LI Hong-li, LIU Chang. Research Progress on Lymphocyte Activation Gene-3 in Gynecological Tumors[J]. Journal of International Obstetrics and Gynecology, 2024, 51(5): 566-571.

Figures/Tables 2

References 43

[1]	Abi-Aad SJ, Zouein J, Chartouni A, et al. Simultaneous inhibition of PD-1 and LAG-3: the future of immunotherapy?[J]. Immunotherapy, 2023, 15(8):611-618. doi: 10.2217/imt-2022-0185.
[2]	李云鹏, 曹英, 陈伟, 等. LAG-3的生物学特点及其在肿瘤免疫中的研究进展[J]. 现代免疫学, 2024, 44(1):55-60.
[3]	Yu L, Sun M, Zhang Q, et al. Harnessing the immune system by targeting immune checkpoints: Providing new hope for Oncotherapy[J]. Front Immunol, 2022,13:982026. doi: 10.3389/fimmu.2022.982026.
[4]	Lythgoe MP, Liu D, Annels NE, et al. Gene of the month: lymphocyte-activation gene 3 (LAG-3)[J]. J Clin Pathol, 2021, 74(9):543-547. doi: 10.1136/jclinpath-2021-207517.
[5]	Wang M, Du Q, Jin J, et al. LAG3 and its emerging role in cancer immunotherapy[J]. Clin Transl Med, 2021, 11(3):e365. doi: 10.1002/ctm2.365. pmid: 33784013
[6]	Alqurashi YE. Lymphocyte-activation gene 3 (LAG-3) as a promising immune checkpoint in cancer immunotherapy: From biology to the clinic[J]. Pathol Res Pract, 2024,254:155124. doi: 10.1016/j.prp.2024.155124.
[7]	Huo JL, Wang YT, Fu WJ, et al. The promising immune checkpoint LAG-3 in cancer immunotherapy: from basic research to clinical application[J]. Front Immunol, 2022,13:956090. doi: 10.3389/fimmu.2022.956090.
[8]	Qian W, Zhao M, Wang R, et al. Fibrinogen-like protein 1 (FGL1): the next immune checkpoint target[J]. J Hematol Oncol, 2021, 14(1):147. doi: 10.1186/s13045-021-01161-8.
[9]	Aigner-Radakovics K, De Sousa Linhares A, Salzer B, et al. The ligand-dependent suppression of TCR signaling by the immune checkpoint receptor LAG3 depends on the cytoplasmic RRFSALE motif[J]. Sci Signal, 2023, 16(805):eadg2610. doi: 10.1126/scisignal.adg2610.
[10]	Ibrahim R, Saleh K, Chahine C, et al. LAG-3 Inhibitors: Novel Immune Checkpoint Inhibitors Changing the Landscape of Immunotherapy[J]. Biomedicines, 2023, 11(7):1878. doi: 10.3390/biomedicines11071878.
[11]	Chocarro L, Blanco E, Zuazo M, et al. Understanding LAG-3 Signaling[J]. Int J Mol Sci, 2021, 22(10):5282. doi: 10.3390/ijms22105282.
[12]	Joller N, Anderson AC, Kuchroo VK. LAG-3, TIM-3, and TIGIT: Distinct functions in immune regulation[J]. Immunity, 2024, 57(2):206-222. doi: 10.1016/j.immuni.2024.01.010. pmid: 38354701
[13]	Gertel S, Polachek A, Elkayam O, et al. Lymphocyte activation gene-3 (LAG-3) regulatory T cells: An evolving biomarker for treatment response in autoimmune diseases[J]. Autoimmun Rev, 2022, 21(6):103085. doi: 10.1016/j.autrev.2022.103085.
[14]	Annunziato F, Manetti R, Cosmi L, et al. Opposite role for interleukin-4 and interferon-gamma on CD30 and lymphocyte activation gene-3 (LAG-3) expression by activated naive T cells[J]. Eur J Immunol, 1997, 27(9):2239-2244. doi: 10.1002/eji.1830270918. pmid: 9341765
[15]	Beumer-Chuwonpad A, Taggenbrock R, Ngo TA, et al. The Potential of Tissue-Resident Memory T Cells for Adoptive Immunotherapy against Cancer[J]. Cells, 2021, 10(9):2234. doi: 10.3390/cells10092234.
[16]	Konstantinopoulos PA, Matulonis UA. Clinical and translational advances in ovarian cancer therapy[J]. Nat Cancer, 2023, 4(9):1239-1257. doi: 10.1038/s43018-023-00617-9.
[17]	Habel A, Weili X, Hadj Ahmed M, et al. Immune checkpoints as potential theragnostic biomarkers for epithelial ovarian cancer[J]. Int J Biol Markers, 2023, 38(3/4):203-213. doi: 10.1177/03936155231186163.
[18]	Kozłowski M, Borzyszkowska D, Cymbaluk-Płoska A. The Role of TIM-3 and LAG-3 in the Microenvironment and Immunotherapy of Ovarian Cancer[J]. Biomedicines, 2022, 10(11):2826. doi: 10.3390/biomedicines10112826.
[19]	Tu L, Guan R, Yang H, et al. Assessment of the expression of the immune checkpoint molecules PD-1, CTLA4, TIM-3 and LAG-3 across different cancers in relation to treatment response, tumor-infiltrating immune cells and survival[J]. Int J Cancer, 2020, 147(2):423-439. doi: 10.1002/ijc.32785. pmid: 31721169
[20]	朱元媛, 闫洪超, 刘永利, 等. BTLA、LAG3和TIM3在上皮性卵巢癌组织中的表达意义[J]. 实用医学杂志, 2019, 35(5):698-702. doi: 10.3969/j.issn.1006-5725.2019.05.005.
[21]	Eurich K, De La Cruz P, Laguna A, et al. Multiplex serum immune profiling reveals circulating LAG-3 is associated with improved patient survival in high grade serous ovarian cancer[J]. Gynecol Oncol, 2023, 174:200-207. doi: 10.1016/j.ygyno.2023.05.015. pmid: 37224792
[22]	Zaitsu S, Yano M, Adachi S, et al. Lymphocyte-activation gene 3 protein expression in tumor-infiltrating lymphocytes is associated with a poor prognosis of ovarian clear cell carcinoma[J]. J Ovarian Res, 2023, 16(1):93. doi: 10.1186/s13048-023-01179-1. pmid: 37179337
[23]	Crosbie EJ, Kitson SJ, McAlpine JN, et al. Endometrial cancer[J]. Lancet, 2022, 399(10333):1412-1428. doi: 10.1016/S0140-6736(22)00323-3. pmid: 35397864
[24]	Gu B, Shang X, Yan M, et al. Variations in incidence and mortality rates of endometrial cancer at the global, regional, and national levels, 1990-2019[J]. Gynecol Oncol, 2021, 161(2):573-580. doi: 10.1016/j.ygyno.2021.01.036. pmid: 33551200
[25]	Zhang C, Wang M, Wu Y. Features of the immunosuppressive tumor microenvironment in endometrial cancer based on molecular subtype[J]. Front Oncol, 2023,13:1278863. doi: 10.3389/fonc.2023.1278863.
[26]	Hong JH, Cho HW, Ouh YT, et al. Lymphocyte activation gene (LAG)-3 is a potential immunotherapeutic target for microsatellite stable, programmed death-ligand 1 (PD-L1)-positive endometrioid endometrial cancer[J]. J Gynecol Oncol, 2023, 34(2):e18. doi: 10.3802/jgo.2023.34.e18.
[27]	Friedman LA, Ring KL, Mills AM. LAG-3 and GAL-3 in Endometrial Carcinoma: Emerging Candidates for Immunotherapy[J]. Int J Gynecol Pathol, 2020, 39(3):203-212. doi: 10.1097/PGP.0000000000000608. pmid: 32267656
[28]	窦倩茹, 范文秀, 王林芳, 等. 子宫内膜癌组织中LAG-3、TIM-3、BTLA的表达情况及意义[J]. 现代预防医学, 2020, 47(2):317-321.
[29]	郭立文, 曹罗元, 陈惠华, 等. 组织内 PGK1、SOCS1、LAG-3 水平与子宫内膜癌病理特征的相关性分析[J]. 临床和实验医学杂志, 2022, 21(24):2624-2628. doi: 10.3969/j.issn.1671-4695.2022.24.013.
[30]	张瑞红, 张海涛. 可溶性T细胞免疫球蛋白黏蛋白3、淋巴细胞激活基因3表达水平与子宫内膜癌疾病转归的相关性[J]. 医学理论与实践, 2023, 36(11):1934-1936. doi: 10.19381/j.issn.1001-7585.2023.11.052.
[31]	Zhang Y, Yang R, Xu C, et al. Analysis of the immune checkpoint lymphocyte activation gene-3 (LAG-3) in endometrial cancer: An emerging target for immunotherapy[J]. Pathol Res Pract, 2022,236:153990. doi: 10.1016/j.prp.2022.153990.
[32]	Schubert M, Bauerschlag DO, Muallem MZ, et al. Challenges in the Diagnosis and Individualized Treatment of Cervical Cancer[J]. Medicina(Kaunas), 2023, 59(5):925. doi: 10.3390/medicina59050925.
[33]	Grau JF, Farinas-Madrid L, Garcia-Duran C, et al. Advances in immunotherapy in cervical cancer[J]. Int J Gynecol Cancer, 2023, 33(3):403-413. doi: 10.1136/ijgc-2022-003758.
[34]	Li Y, Shen F, Tan Q, et al. Research Progress of Immuno-Inhibitory Receptors in Gynecological Cervical Cancer[J]. Technol Cancer Res Treat, 2023,22:15330338231208846. doi: 10.1177/15330338231208846.
[35]	Hung AL, Maxwell R, Theodros D, et al. TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM[J]. Oncoimmunology, 2018, 7(8):e1466769. doi: 10.1080/2162402X.2018.1466769.
[36]	Qi Y, Chen L, Liu Q, et al. Research Progress Concerning Dual Blockade of Lymphocyte-Activation Gene 3 and Programmed Death-1/Programmed Death-1 Ligand-1 Blockade in Cancer Immunotherapy: Preclinical and Clinical Evidence of This Potentially More Effective Immunotherapy Strategy[J]. Front Immunol, 2020, 11:563258. doi: 10.3389/fimmu.2020.563258.
[37]	Lichtenegger FS, Rothe M, Schnorfeil FM, et al. Targeting LAG-3 and PD-1 to Enhance T Cell Activation by Antigen-Presenting Cells[J]. Front Immunol, 2018,9:385. doi: 10.3389/fimmu.2018.00385.
[38]	李玉英, 赵丽, 王蕾, 等. 子宫颈鳞状细胞癌组织TIM-3、LAG-3、TIGIT的表达变化及其意义[J]. 山东医药, 2022, 62(18):12-16. doi: 10.3969/j.issn.1002-266X.2022.18.003.
[39]	Li Y, Wang W, Tian J, et al. Clinical Significance of Soluble LAG-3 (sLAG-3) in Patients With Cervical Cancer Determined via Enzyme-Linked Immunosorbent Assay With Monoclonal Antibodies[J]. Technol Cancer Res Treat, 2023,22:15330338231202650. doi: 10.1177/15330338231202650.
[40]	Heeren AM, Rotman J, Stam A, et al. Efficacy of PD-1 blockade in cervical cancer is related to a CD8⁺FoxP3⁺CD25⁺ T-cell subset with operational effector functions despite high immune checkpoint levels[J]. J Immunother Cancer, 2019, 7(1):43. doi: 10.1186/s40425-019-0526-z. pmid: 30755279
[41]	Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma[J]. N Engl J Med, 2022, 386(1):24-34. doi: 10.1056/NEJMoa2109970.
[42]	Long GV, Stephen Hodi F, Lipson EJ, et al. Overall Survival and Response with Nivolumab and Relatlimab in Advanced Melanoma[J]. NEJM Evid, 2023, 2(4):EVIDoa2200239. doi: 10.1056/EVIDoa2200239.
[43]	Chocarro L, Blanco E, Arasanz H, et al. Clinical landscape of LAG-3-targeted therapy[J]. Immunooncol Technol, 2022,14:100079. doi: 10.1016/j.iotech.2022.100079.

药物名称	药物类型	组合剂	阶段	临床试验编号	状态	研究结果
Relatlimab（BMS986016）	抗LAG-3	Ipilimumab, Cyclophosphamid, Fludarabine Phosphate, Tumor Infiltrating Lymphocytes infusion, Nivolumab	Ⅰ，Ⅱ	NCT04611126	完成（2024-07-02）	尚未提交
Tebotelimab（MGD013）	抗PD-1和抗LAG-3	Margetuximab（抗HER2）	Ⅰ	NCT03219268	完成（2023-02-08）	尚未提交
INCAGN02385	抗LAG-3	-	Ⅰ	NCT03538028	完成（2020-10-07）	尚未提交
Relatlimab（BMS986016）	抗LAG-3	Adavosertib, Afatinib, Dimaleate, Nivolumab, Osimertinib, Palbociclib, Pertuzumab, PI3K-beta, FGFR Inhibitor AZD4547	Ⅱ	NCT02465060	进行（估计2025-12）	尚未提交
XmAb22841	抗CTLA-4和抗LAG-3	Pembrolizumab（抗PD-1）	Ⅰ	NCT03849469	完成（2023-02-16）	尚未提交
LAG-525	抗LAG-3	PDR001型（抗PD-1）	Ⅱ	NCT03365791	完成（2020-09-17）	已公布
BMS986016	抗LAG-3	抗PD-1	Ⅰ	NCT01968109	招募	尚未提交

药物名称	药物类型	组合剂	阶段	临床试验编号	状态	研究结果
Relatlimab（BMS986016）	抗LAG-3	Ipilimumab, Cyclophosphamid, Fludarabine Phosphate, Tumor Infiltrating Lymphocytes infusion, Nivolumab	Ⅰ，Ⅱ	NCT04611126	完成（2024-07-02）	尚未提交
Tebotelimab（MGD013）	抗PD-1和抗LAG-3	Margetuximab（抗HER2）	Ⅰ	NCT03219268	完成（2023-02-08）	尚未提交
INCAGN02385	抗LAG-3	-	Ⅰ	NCT03538028	完成（2020-10-07）	尚未提交
Relatlimab（BMS986016）	抗LAG-3	Adavosertib, Afatinib, Dimaleate, Nivolumab, Osimertinib, Palbociclib, Pertuzumab, PI3K-beta, FGFR Inhibitor AZD4547	Ⅱ	NCT02465060	进行（估计2025-12）	尚未提交
XmAb22841	抗CTLA-4和抗LAG-3	Pembrolizumab（抗PD-1）	Ⅰ	NCT03849469	完成（2023-02-16）	尚未提交
LAG-525	抗LAG-3	PDR001型（抗PD-1）	Ⅱ	NCT03365791	完成（2020-09-17）	已公布
BMS986016	抗LAG-3	抗PD-1	Ⅰ	NCT01968109	招募	尚未提交

药物名称	药物类型	联合	阶段	临床试验编号	状态	研究结果
Tebotelimab（MGD013）	抗PD-1和抗LAG-3	Margetuximab（抗HER2）	Ⅰ	NCT03219268	完成（2023-02-08）	尚未提交
XmAb22841	抗CTLA-4和抗LAG-3	Pembrolizumab（抗PD-1）	Ⅰ	NCT03849469	完成（2023-02-16）	尚未提交
Relatlimab	抗LAG-3	抗PD-1	Ⅰ，Ⅱ	NCT02488759	招募	-
INCAGN02385	抗LAG-3	-	Ⅰ	NCT03538028	完成（2020-10-07）	尚未提交
INCAGN02385	抗LAG-3	抗PD-1	Ⅰ，Ⅱ	NCT01968109	招募	-

药物名称	药物类型	联合	阶段	临床试验编号	状态	研究结果
Tebotelimab（MGD013）	抗PD-1和抗LAG-3	Margetuximab（抗HER2）	Ⅰ	NCT03219268	完成（2023-02-08）	尚未提交
XmAb22841	抗CTLA-4和抗LAG-3	Pembrolizumab（抗PD-1）	Ⅰ	NCT03849469	完成（2023-02-16）	尚未提交
Relatlimab	抗LAG-3	抗PD-1	Ⅰ，Ⅱ	NCT02488759	招募	-
INCAGN02385	抗LAG-3	-	Ⅰ	NCT03538028	完成（2020-10-07）	尚未提交
INCAGN02385	抗LAG-3	抗PD-1	Ⅰ，Ⅱ	NCT01968109	招募	-