SerpinB9与肿瘤关系及其在皮肤肿瘤领域的研究进展Relationship Between SerpinB9 and Tumors and Research Progress of SerpinB9 in Skin Tumors
张姗;刘兆睿;刘洁;
ZHANG Shan;LIU Zhaorui;LIU Jie;Department of Dermatology,National Clinical Research Center for Dermatologic and Immunologic Diseases,Chinese Academy of Medical Sciences & Peking Union Medical College;State Key Laboratory of Complex Severe and Rare Diseases,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences & Peking Union Medical College;
摘要(Abstract):
死亡受体途径和穿孔素/颗粒酶途径是免疫系统杀伤肿瘤细胞的主要机制,SerpinB9是已知的人体中唯一能够抑制颗粒酶B(granzyme B,GrB)水解活性的蛋白。研究表明,肺癌、前列腺癌等肿瘤细胞可通过表达SerpinB9抵抗细胞毒性淋巴细胞通过穿孔素/GrB介导的杀伤作用。在皮肤肿瘤领域,恶性黑色素瘤、鳞状细胞癌及皮肤淋巴肿瘤细胞中均可检测到SerpinB9表达,并通过促进免疫逃逸、抵抗免疫治疗、影响肿瘤微环境等多种途径促进肿瘤进展。此外,已有研究证实SerpinB9抑制剂可抑制恶性黑色素瘤生长,表明SerpinB9可作为潜在的抗肿瘤治疗靶点。本文将对SerpinB9在皮肤肿瘤领域的研究现状进行综述。
Death receptor pathway and perforin/granzyme pathway are the main mechanisms for immune system to kill tumor cells. SerpinB9 is the only known human protein that is able to inhibit the proteolytic activity of granzyme B(GrB). Expression of SerpinB9 has been observed in various human tumors, such as lung cancer and prostate cancer, and SerpinB9 can protect tumor cells from cytotoxic lymphocytes-mediated killing through the perforin/GrB pathway. In skin tumors, SerpinB9 expression has been detected in cells of malignant melanoma, cutaneous squamous cell carcinoma, cutaneous lymphomas, in which SerpinB9 contributes to tumor progression by mediating immune escape, resistance to immunotherapy and interference of the tumor microenvironment. In addition, researches have shown that inhibitor of SerpinB9 could retard the growth of melanoma, indicating the potential anti-tumor therapeutic application of SerpinB9 inhibition. The research status of SerpinB9 in skin tumors is reviewed in this paper.
关键词(KeyWords):
SerpinB9;皮肤肿瘤;肿瘤免疫;恶性黑色素瘤;皮肤淋巴瘤
SerpinB9;skin tumor;tumor immunity;melanoma;cutaneous lymphoma
基金项目(Foundation): 国家自然科学基金(82173449);; 中国医学科学院中央级公益性科研院所基本科研业务费专项资金(2019XK320024)~~
作者(Authors):
张姗;刘兆睿;刘洁;
ZHANG Shan;LIU Zhaorui;LIU Jie;Department of Dermatology,National Clinical Research Center for Dermatologic and Immunologic Diseases,Chinese Academy of Medical Sciences & Peking Union Medical College;State Key Laboratory of Complex Severe and Rare Diseases,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences & Peking Union Medical College;
参考文献(References):
- [1] Irving JA,Pike RN,Lesk AM,et al.Phylogeny of the Serpin Superfamily:Implications of Patterns of Amino Acid Conservation for Structure and Function[J].Genome Res,2000,10:1845- 1864.
- [2] Kaiserman D,Bird PI.Control of Granzymes by Serpins[J].Cell Death Differ,2010,17:586- 595.
- [3] Silverman GA,Whisstock JC,Askew DJ,et al.Human Clade B Serpins (Ov-serpins) Belong to a Cohort of Evolutionarily Dispersed Intracellular Proteinase Inhibitor Clades That Protect Cells From Promiscuous Proteolysis[J].Cell Mol Life Sci,2004,61:301- 325.
- [4] Wang WJ,Wang J,Ouyang C,et al.Overview of serpin B9 and its roles in cancer (Review)[J].Oncol Rep,2021,46:190.
- [5] Medema JP,de Jong J,Peltenburg LT,et al.Blockade of the Granzyme B/Perforin Pathway Through Overexpression of the Serine Protease Inhibitor PI- 9/SPI- 6 Constitutes a Mechanism for Immune Escape by Tumors[J].Proc Natl Acad Sci U S A,2001,98:11515- 11520.
- [6] Sun JR,Bird CH,Sutton V,et al.A Cytosolic Granzyme B Inhibitor Related to the Viral Apoptotic Regulator Cytokine Response Modifier A Is Present in Cytotoxic Lymphocytes[J].J Biol Chem,1996,271:27802- 27809.
- [7] Zhang ML,Park SM,Wang Y,et al.Serine Protease Inhibitor 6 Protects Cytotoxic T Cells From Self-inflicted Injury by Ensuring the Integrity of Cytotoxic Granules[J].Immunity,2006,24:451- 461.
- [8] Ansari AW,Temblay JN,Alyahya SH,et al.Serine Protease Inhibitor 6 Protects iNKT Cells From Self-inflicted Damage[J].J Immunol,2010,185:877- 883.
- [9] Bird CH,Sutton VR,Sun J,et al.Selective Regulation of Apoptosis:the Cytotoxic Lymphocyte Serpin Proteinase Inhibitor 9 Protects Against Granzyme B-mediated Apoptosis Without Perturbing the Fas Cell Death Pathway[J].Mol Cell Biol,1998,18:6387- 6398.
- [10] Kummer JA,Micheau O,Schneider P,et al.Ectopic Expression of the Serine Protease Inhibitor PI9 Modulates Death Receptor-mediated Apoptosis[J].Cell Death Differ,2007,14:1486- 1496.
- [11] Cunningham TD,Jiang XG,Shapiro DJ.Expression of High Levels of Human Proteinase Inhibitor 9 Blocks Both Perforin/Granzyme and Fas/Fas Ligand-mediated Cytotoxi-city[J].Cell Immunol,2007,245:32- 41.
- [12] Bladergroen BA,Strik MC,Bovenschen N,et al.The Granzyme B Inhibitor,Protease Inhibitor 9,Is Mainly Expressed by Dendritic Cells and at Immune-privileged Sites[J].J Immunol,2001,166:3218- 3225.
- [13] Azzi J,Skartsis N,Mounayar M,et al.Serine Protease Inhibitor 6 Plays a Critical Role in Protecting Murine Granzyme B-producing Regulatory T Cells[J].J Immunol,2013,191:2319- 2327.
- [14] Bladergroen BA,Strik MCM,Wolbink AM,et al.The Granzyme B Inhibitor Proteinase Inhibitor 9 (PI9) Is Expressed by Human Mast Cells[J].Eur J Immunol,2005,35:1175- 1183.
- [15] Buzza MS,Hirst CE,Bird CH,et al.The Granzyme B Inhibitor,PI- 9,Is Present in Endothelial and Mesothelial Cells,Suggesting That It Protects Bystander Cells During Immune Responses[J].Cell Immunol,2001,210:21- 29.
- [16] Rizzitelli A,Meuter S,Vega Ramos J,et al.Serpinb9 (Spi6)-deficient Mice Are Impaired in Dendritic Cell-mediated Antigen Cross-presentation[J].Immunol Cell Biol,2012,90:841- 851.
- [17] Garrido F.MHC/HLA Class I Loss in Cancer Cells[J].Adv Exp Med Biol,2019,1151:15- 78.
- [18] Rousalova I,Krepela E,Prochazka J,et al.Expression of Proteinase Inhibitor- 9/serpinB9 in Non-small Cell Lung Carcinoma Cells and Tissues[J].Int J Oncol,2010,36:275- 283.
- [19] Soriano C,Mukaro V,Hodge G,et al.Increased Proteinase Inhibitor- 9 (PI- 9) and Reduced Granzyme B in Lung Cancer:Mechanism for Immune Evasion?[J].Lung Cancer,2012,77:38- 45.
- [20] Zhou B,Chen EL,Chen JH,et al.Overexpression of Proteinase Inhibitor 9 Is Associated With Poor Prognosis in Human Hepatocellular Carcinoma and With Proliferation and Apoptosis in HepG2 Cells in vitro[J].Int J Clin Exp Pathol,2019,12:3719- 3727.
- [21] Vycital O,Pitule P,Hosek P,et al.Expression of Serpin B9 as a Prognostic Factor of Colorectal Cancer[J].Anticancer Res,2019,39:6063- 6066.
- [22] Ray M,Hostetter DR,Loeb CRK,et al.Inhibition of Granzyme B by PI- 9 protects prostate cancer cells from apoptosis[J].Prostate,2012,72:846- 855.
- [23] Fritsch K,Finke J,Grüllich C.Suppression of Granzyme B Activity and Caspase- 3 Activation in Leukaemia Cells Constitutively Expressing the Protease Inhibitor 9[J].Ann Hematol,2013,92:1603- 1609.
- [24] Chen Y,Quan LN,Jia CM,et al.Proteomics-Based Approach Reveals the Involvement of SERPINB9 in Recurrent and Relapsed Multiple Myeloma[J].J Proteome Res,2021,20:2673- 2686.
- [25] van Houdt IS,Oudejans JJ,van den Eertwegh AJM,et al.Expression of the Apoptosis Inhibitor Protease Inhibitor 9 Predicts Clinical Outcome in Vaccinated Patients With Stage Ⅲ and Ⅳ Melanoma[J].Clin Cancer Res,2005,11:6400- 6407.
- [26] Van Allen EM,Miao DN,Schilling B,et al.Genomic Correlates of Response to CTLA- 4 Blockade in Metastatic Melanoma[J].Science,2015,350:207- 211.
- [27] Jiang P,Gu SQ,Pan D,et al.Signatures of T cell Dysfunction and Exclusion Predict Cancer Immunotherapy Response[J].Nat Med,2018,24:1550- 1558.
- [28] Jiang XJ,Wang J,Deng XY,et al.Role of the Tumor Microenvironment in PD- L1/PD- 1-mediated Tumor Immune Escape[J].Mol Cancer,2019,18:10.
- [29] Jiang LW,Wang YJ,Zhao J,et al.Direct Tumor Killing and Immunotherapy through Anti-SerpinB9 Therapy[J].Cell,2020,183:1219- 1233.e18.
- [30] Liu Y,Cao XT.Immunosuppressive Cells in Tumor Immune Escape and Metastasis[J].J Mol Med (Berl),2016,94:509- 522.
- [31] Luo H,Ma C.Identification of Prognostic Genes in Uveal Melanoma Microenvironment[J].PLoS One,2020,15:e0242263.
- [32] Peters FS,Peeters AMA,van den Bosch TPP,et al.Disrupted Regulation of serpinB9 in Circulating T Cells Is Associated With an Increased Risk for Post-transplant Skin Cancer[J].Clin Exp Immunol,2019,197:341- 351.
- [33] Bladergroen BA,Meijer CJLM,ten Berge RL,et al.Expression of the Granzyme B Inhibitor,Protease Inhibitor 9,by Tumor Cells in Patients With non-Hodgkin and Hodgkin Lymphoma:a Novel Protective Mechanism for Tumor Cells to Circumvent the Immune System?[J].Blood,2002,99:232- 237.
- [34] ten Berge RL,Meijer CJLM,Dukers DF,et al.Expression Levels of Apoptosis-related Proteins Predict Clinical Outcome in Anaplastic Large Cell Lymphoma[J].Blood,2002,99:4540- 4546.
- [35] Bossard C,Belhadj K,Reyes F,et al.Expression of the Granzyme B Inhibitor PI9 Predicts Outcome in Nasal NK/T-cell Lymphoma:Results of a Western Series of 48 Patients Treated With First-line Polychemotherapy Within the Grouped'Etude des Lymphomes de l'Adulte (GELA) Trials[J].Blood,2007,109:2183- 2189.
- 张姗
- 刘兆睿
- 刘洁
ZHANG Shan- LIU Zhaorui
- LIU Jie
- Department of Dermatology
- National Clinical Research Center for Dermatologic and Immunologic Diseases
- Chinese Academy of Medical Sciences & Peking Union Medical College
- State Key Laboratory of Complex Severe and Rare Diseases
- Peking Union Medical College Hospital
- Chinese Academy of Medical Sciences & Peking Union Medical College
- 张姗
- 刘兆睿
- 刘洁
ZHANG Shan- LIU Zhaorui
- LIU Jie
- Department of Dermatology
- National Clinical Research Center for Dermatologic and Immunologic Diseases
- Chinese Academy of Medical Sciences & Peking Union Medical College
- State Key Laboratory of Complex Severe and Rare Diseases
- Peking Union Medical College Hospital
- Chinese Academy of Medical Sciences & Peking Union Medical College