{"title":"谷氨酰胺酶表达与免疫抑制性肿瘤微环境、临床病理特征和子宫内膜癌临床预后的关系","authors":"Shiho Asaka, Neha Verma, Ting-Tai Yen, Jessica L Hicks, Hiro Nonogaki, Yao-An Shen, Jiaxin Hong, Ryoichi Asaka, Angelo M DeMarzo, Tian-Li Wang, Ie-Ming Shih, Stephanie Gaillard","doi":"10.1136/ijgc-2024-005920","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>Increased glutamine metabolism by cancer cells via upregulation of the drug-targetable enzyme glutaminase may contribute to an immune-suppressive tumor microenvironment. Inhibiting glutamine metabolism can not only suppress tumor growth, but also enhance tumor-specific immunity. We investigated the relationship between glutaminase expression, the immune tumor microenvironment, and clinicopathologic features in endometrial cancer.</p><p><strong>Methods: </strong>Tissue microarrays constructed from 87 primary endometrial cancer specimens were stained by immunohistochemistry for glutaminase, c-Myc, mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6), postmeiotic segregation increased 2 (PMS2), estrogen receptor (ER), progresterone receptor (PR), CD8, FoxP3, CD68, programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1). We compared the immune tumor microenvironment and clinicopathologic features between glutaminase-high (H-score≥median) versus glutaminase-low (H-score<median) endometrial cancers. We also evaluated data from The Cancer Genome Atlas (TCGA) for 527 endometrial cancer patients in whom RNA-Seq for glutaminase expression was performed and compared long-term clinical outcomes between glutaminase-high (RNA-Seq Z-score≥median) versus glutaminase-low (RNA-Seq score<median) patients.</p><p><strong>Results: </strong>In the tissue microarray analysis, glutaminase expression was positively correlated with c-Myc expression (r=0.4226, p<0.0001). Glutaminase-high endometrial cancers were associated with non-endometrioid histology (p=0.0001), high histologic grade (p=0.0004), myometrial invasion (p=0.017), advanced stage (p=0.012), increased FoxP3<sup>+</sup> regulatory T cells (p=0.008), increased CD68<sup>+</sup> tumor-associated macrophages (p=0.010), and higher PD-L1 combined positive scores (p=0.043). In the TCGA analysis, glutaminase-high (RNA-Seq Z-score≥median) patients showed worse overall (p=0.004) and progression-free (p=0.032) survival than glutaminase-low (RNA-Seq score<median) patients.</p><p><strong>Conclusions: </strong>Our findings indicate that increased glutaminase expression is associated with an immune-suppressive tumor microenvironment, poor clinicopathologic features, and worse long-term outcomes in patients with endometrial cancer.</p>","PeriodicalId":14097,"journal":{"name":"International Journal of Gynecological Cancer","volume":" ","pages":"1737-1744"},"PeriodicalIF":4.1000,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11560285/pdf/","citationCount":"0","resultStr":"{\"title\":\"Association of glutaminase expression with immune-suppressive tumor microenvironment, clinicopathologic features, and clinical outcomes in endometrial cancer.\",\"authors\":\"Shiho Asaka, Neha Verma, Ting-Tai Yen, Jessica L Hicks, Hiro Nonogaki, Yao-An Shen, Jiaxin Hong, Ryoichi Asaka, Angelo M DeMarzo, Tian-Li Wang, Ie-Ming Shih, Stephanie Gaillard\",\"doi\":\"10.1136/ijgc-2024-005920\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>Increased glutamine metabolism by cancer cells via upregulation of the drug-targetable enzyme glutaminase may contribute to an immune-suppressive tumor microenvironment. Inhibiting glutamine metabolism can not only suppress tumor growth, but also enhance tumor-specific immunity. We investigated the relationship between glutaminase expression, the immune tumor microenvironment, and clinicopathologic features in endometrial cancer.</p><p><strong>Methods: </strong>Tissue microarrays constructed from 87 primary endometrial cancer specimens were stained by immunohistochemistry for glutaminase, c-Myc, mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6), postmeiotic segregation increased 2 (PMS2), estrogen receptor (ER), progresterone receptor (PR), CD8, FoxP3, CD68, programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1). We compared the immune tumor microenvironment and clinicopathologic features between glutaminase-high (H-score≥median) versus glutaminase-low (H-score<median) endometrial cancers. We also evaluated data from The Cancer Genome Atlas (TCGA) for 527 endometrial cancer patients in whom RNA-Seq for glutaminase expression was performed and compared long-term clinical outcomes between glutaminase-high (RNA-Seq Z-score≥median) versus glutaminase-low (RNA-Seq score<median) patients.</p><p><strong>Results: </strong>In the tissue microarray analysis, glutaminase expression was positively correlated with c-Myc expression (r=0.4226, p<0.0001). Glutaminase-high endometrial cancers were associated with non-endometrioid histology (p=0.0001), high histologic grade (p=0.0004), myometrial invasion (p=0.017), advanced stage (p=0.012), increased FoxP3<sup>+</sup> regulatory T cells (p=0.008), increased CD68<sup>+</sup> tumor-associated macrophages (p=0.010), and higher PD-L1 combined positive scores (p=0.043). In the TCGA analysis, glutaminase-high (RNA-Seq Z-score≥median) patients showed worse overall (p=0.004) and progression-free (p=0.032) survival than glutaminase-low (RNA-Seq score<median) patients.</p><p><strong>Conclusions: </strong>Our findings indicate that increased glutaminase expression is associated with an immune-suppressive tumor microenvironment, poor clinicopathologic features, and worse long-term outcomes in patients with endometrial cancer.</p>\",\"PeriodicalId\":14097,\"journal\":{\"name\":\"International Journal of Gynecological Cancer\",\"volume\":\" \",\"pages\":\"1737-1744\"},\"PeriodicalIF\":4.1000,\"publicationDate\":\"2024-11-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11560285/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"International Journal of Gynecological Cancer\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1136/ijgc-2024-005920\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"OBSTETRICS & GYNECOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Gynecological Cancer","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1136/ijgc-2024-005920","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"OBSTETRICS & GYNECOLOGY","Score":null,"Total":0}
Association of glutaminase expression with immune-suppressive tumor microenvironment, clinicopathologic features, and clinical outcomes in endometrial cancer.
Objective: Increased glutamine metabolism by cancer cells via upregulation of the drug-targetable enzyme glutaminase may contribute to an immune-suppressive tumor microenvironment. Inhibiting glutamine metabolism can not only suppress tumor growth, but also enhance tumor-specific immunity. We investigated the relationship between glutaminase expression, the immune tumor microenvironment, and clinicopathologic features in endometrial cancer.
Methods: Tissue microarrays constructed from 87 primary endometrial cancer specimens were stained by immunohistochemistry for glutaminase, c-Myc, mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6), postmeiotic segregation increased 2 (PMS2), estrogen receptor (ER), progresterone receptor (PR), CD8, FoxP3, CD68, programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1). We compared the immune tumor microenvironment and clinicopathologic features between glutaminase-high (H-score≥median) versus glutaminase-low (H-score
Results: In the tissue microarray analysis, glutaminase expression was positively correlated with c-Myc expression (r=0.4226, p<0.0001). Glutaminase-high endometrial cancers were associated with non-endometrioid histology (p=0.0001), high histologic grade (p=0.0004), myometrial invasion (p=0.017), advanced stage (p=0.012), increased FoxP3+ regulatory T cells (p=0.008), increased CD68+ tumor-associated macrophages (p=0.010), and higher PD-L1 combined positive scores (p=0.043). In the TCGA analysis, glutaminase-high (RNA-Seq Z-score≥median) patients showed worse overall (p=0.004) and progression-free (p=0.032) survival than glutaminase-low (RNA-Seq score
Conclusions: Our findings indicate that increased glutaminase expression is associated with an immune-suppressive tumor microenvironment, poor clinicopathologic features, and worse long-term outcomes in patients with endometrial cancer.
期刊介绍：
The International Journal of Gynecological Cancer, the official journal of the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology, is the primary educational and informational publication for topics relevant to detection, prevention, diagnosis, and treatment of gynecologic malignancies. IJGC emphasizes a multidisciplinary approach, and includes original research, reviews, and video articles. The audience consists of gynecologists, medical oncologists, radiation oncologists, radiologists, pathologists, and research scientists with a special interest in gynecological oncology.
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