{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:23:58Z","timestamp":1787027038341,"version":"build-2736575974"},"reference-count":142,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,22]],"date-time":"2022-08-22T00:00:00Z","timestamp":1661126400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>Endometrial cancer is rising in prevalence. The standard treatment modality of hysterectomy is becoming increasingly inadequate due primarily to the direct link between endometrial cancer and high BMI which increases surgical risks. This is an immunogenic cancer, with unique molecular subtypes associated with differential immune infiltration. Despite the immunogenicity of endometrial cancer, there is limited pre-clinical and clinical evidence of the function of immune cells in both the normal and cancerous endometrium. Immune checkpoint inhibitors for endometrial cancer are the most well studied type of immune therapy but these are not currently used as standard-of-care and importantly, they represent only one method of immune manipulation. There is limited evidence regarding the use of other immunotherapies as surgical adjuvants or alternatives. Levonorgestrel-loaded intra-uterine systems can also be effective for early-stage disease, but with varying success. There is currently no known reason as to what predisposes some patients to respond while others do not. As hormones can directly influence immune cell function, it is worth investigating the immune compartment in this context. This review assesses the immunological components of the endometrium and describes how the immune microenvironment changes with hormones, obesity, and in progression to malignancy. It also describes the importance of investigating novel pathways for immunotherapy.<\/jats:p>","DOI":"10.3389\/fonc.2022.975201","type":"journal-article","created":{"date-parts":[[2022,8,22]],"date-time":"2022-08-22T02:12:31Z","timestamp":1661134351000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":24,"title":["Importance of the endometrial immune environment in endometrial cancer and associated therapies"],"prefix":"10.3389","volume":"12","author":[{"given":"Hannah","family":"van der Woude","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn Elizabeth","family":"Hally","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret Jane","family":"Currie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Gasser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire Elizabeth","family":"Henry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA: A Cancer J Clin"},{"key":"B2","unstructured":"New cancer registrations 20182020"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20210042","article-title":"Suppressive effects of the obese tumor microenvironment on Cd8 T cell infiltration and effector function","volume":"219","author":"Dyck","year":"2022","journal-title":"J Exp Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2021.01.029","article-title":"Complete pathological response following levonorgestrel intrauterine device in clinically stage 1 endometrial adenocarcinoma: Results of a randomized clinical trial","volume":"161","author":"Janda","year":"2021","journal-title":"Gynecol Oncol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1186\/s40364-021-00301-z","article-title":"Immunotherapy in endometrial cancer: Rationale, practice and perspectives","volume":"9","author":"Cao","year":"2021","journal-title":"Biomark Res"},{"key":"B6","volume-title":"Endometrial hyperplasia","author":"Sing","year":"2021"},{"key":"B7","doi-asserted-by":"publisher","first-page":"S25","DOI":"10.1097\/pgp.0000000000000512","article-title":"Issues in the differential diagnosis of uterine low-grade endometrioid carcinoma, including mixed endometrial carcinomas: Recommendations from the international society of gynecological pathologists","author":"Rabban","year":"2019","journal-title":"Int J Gynecol Pathol"},{"key":"B8","volume-title":"Endometrial cancer","author":"Casey","year":"2020"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-020117-043609","article-title":"Molecular genetics of endometrial carcinoma","volume":"14","author":"Bell","year":"2019","journal-title":"Annu Rev Pathol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2013.02.023","article-title":"Etiologic heterogeneity in endometrial cancer: Evidence from a gynecologic oncology group trial","volume":"129","author":"Brinton","year":"2013","journal-title":"Gynecol Oncol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1038\/nature12113","article-title":"Integrated genomic characterization of endometrial carcinoma","volume":"497","author":"Kandoth","year":"2013","journal-title":"Nature"},{"key":"B12","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1038\/bjc.2015.190","article-title":"A clinically applicable molecular-based classification for endometrial cancers","volume":"113","author":"Talhouk","year":"2015","journal-title":"Br J Cancer"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3390\/curroncol29020063","article-title":"Endometrial cancer: Transitioning from histology to genomics","volume":"29","author":"Mitric","year":"2022","journal-title":"Curr Oncol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/s1470-2045(18)30079-2","article-title":"Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (Portec-3): Final results of an international, open-label, multicentre, randomised, phase 3 trial","volume":"19","author":"de Boer","year":"2018","journal-title":"Lancet Oncol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1200\/jco.20.00549","article-title":"Molecular classification of the portec-3 trial for high-risk endometrial cancer: Impact on prognosis and benefit from adjuvant therapy","volume":"38","author":"Le\u00f3n-Castillo","year":"2020","journal-title":"J Clin Oncol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"16","DOI":"10.4110\/in.2015.15.1.16","article-title":"Immune cells in the female reproductive tract","volume":"15","author":"Lee","year":"2015","journal-title":"Immune Netw"},{"key":"B17","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1620\/tjem.250.49","article-title":"Endometrial immunity for embryo implantation and pregnancy establishment","volume":"250","author":"Kitazawa","year":"2020","journal-title":"Tohoku J Exp Med"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2015.01.018","article-title":"Estrogen receptors regulate innate immune cells and signaling pathways","volume":"294","author":"Kovats","year":"2015","journal-title":"Cell Immunol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.imlet.2004.10.007","article-title":"Differential estrogen receptor gene expression in human peripheral blood mononuclear cell populations","volume":"97","author":"Phiel","year":"2005","journal-title":"Immunol Lett"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.81.4.8636358","article-title":"Progesterone stimulates the induction of human endometrial Cd56+ lymphocytes in an in vitro culture system","volume":"81","author":"Inoue","year":"1996","journal-title":"J Clin Endocrinol Metab"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.humrep.a019300","article-title":"Evaluation of oestrogen and progesterone receptor expression in uterine mucosal lymphocytes","volume":"11","author":"King","year":"1996","journal-title":"Hum Reprod"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.51.2.121","article-title":"Endometrial leucocytes: Expression of steroid hormone receptors","volume":"51","author":"Stewart","year":"1998","journal-title":"J Clin Pathol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201445404","article-title":"Progesterone promotes maternal-fetal tolerance by reducing human maternal T-cell polyfunctionality and inducing a specific cytokine profile","volume":"45","author":"Lissauer","year":"2015","journal-title":"Eur J Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.672168","article-title":"Progesterone dampens immune responses in in vitro activated Cd4+ t cells and affects genes associated with autoimmune diseases that improve during pregnancy","volume":"12","author":"Hellberg","year":"2021","journal-title":"Front Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1210\/endocr\/bqaa127","article-title":"Estradiol, progesterone, immunomodulation, and covid-19 outcomes","volume":"161","author":"Mauvais-Jarvis","year":"2020","journal-title":"Endocrinology"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2017.35","article-title":"Progesterone-based compounds affect immune responses and susceptibility to infections at diverse mucosal sites","volume":"10","author":"Hall","year":"2017","journal-title":"Mucosal Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.90","article-title":"Sex differences in immune responses","volume":"16","author":"Klein","year":"2016","journal-title":"Nat Rev Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1677\/joe.1.06565","article-title":"Expression and localization of the progesterone receptor in mouse and human reproductive organs","volume":"191","author":"Teilmann","year":"2006","journal-title":"J Endocrinol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1677\/joe-07-0317","article-title":"Expression of membrane progesterone receptors on human T lymphocytes and jurkat cells and activation of G-proteins by progesterone","volume":"196","author":"Dosiou","year":"2008","journal-title":"J Endocrinol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1617115114","article-title":"Glucocorticoid receptor in T cells mediates protection from autoimmunity in pregnancy","volume":"114","author":"Engler","year":"2017","journal-title":"Proc Natl Acad Sci USA"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1111\/aji.13084","article-title":"Progesterone modulates the T-cell response via glucocorticoid receptor-dependent pathways","volume":"81","author":"Hierweger","year":"2019","journal-title":"Am J Reprod Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0897.1999.tb00107.x","article-title":"Progesterone directly and indirectly affects perforin expression in cytolytic cells","volume":"42","author":"Laskarin","year":"1999","journal-title":"Am J Reprod Immunol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1093\/molehr\/6.10.899","article-title":"In-vitro studies of the potential role of neutrophils in the process of menstruation","volume":"6","author":"Lathbury","year":"2000","journal-title":"MHR: Basic Sci Reprod Med"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/srep36748","article-title":"Evidence for a dynamic role for mononuclear phagocytes during endometrial repair and remodelling","volume":"6","author":"Cousins","year":"2016","journal-title":"Sci Rep"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1101\/gad.9.18.2266","article-title":"Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities","volume":"9","author":"Lydon","year":"1995","journal-title":"Genes Dev"},{"key":"B36","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1095\/biolreprod62.1.85","article-title":"Progesterone inhibits activation of latent matrix metalloproteinase (Mmp)-2 by membrane-type 1 mmp: Enzymes coordinately expressed in human endometrium","volume":"62","author":"Zhang","year":"2000","journal-title":"Biol Reprod"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/S0015-0282(00)00555-0","article-title":"Neutrophils infiltrating the endometrium express vascular endothelial growth factor: Potential role in endometrial angiogenesis","volume":"74","author":"Mueller","year":"2000","journal-title":"Fertil Steril"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02387","article-title":"Uterine immunity and microbiota: A shifting paradigm","volume":"10","author":"Agostinis","year":"2019","journal-title":"Front Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0897.1997.tb00311.x","article-title":"Flow cytometric analysis of leukocytes in the human female reproductive tract: Comparison of fallopian tube, uterus, cervix, and vagina","volume":"38","author":"Givan","year":"1997","journal-title":"Am J Reprod Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1111\/j.8755-8920.2000.430405.x","article-title":"Menstrual cycle dependent fluctuations in nk and T-lymphocyte subsets from non-pregnant human endometrium","volume":"43","author":"Flynn","year":"2000","journal-title":"Am J Reprod Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.3.1869","article-title":"Endometrial nk cells are special immature cells that await pregnancy","volume":"181","author":"Manaster","year":"2008","journal-title":"J Immunol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0165-0378(99)00002-9","article-title":"Menstruation: Induction by matrix metalloproteinases and inflammatory cells","volume":"44","author":"Salamonsen L","year":"1999","journal-title":"J Reprod Immunol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0897.2004.00201.x","article-title":"Endometrial and peritoneal macrophages: Expression of activation and adhesion molecules","volume":"52","author":"Eidukaite","year":"2004","journal-title":"Am J Reprod Immunol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1002\/jlb.61.4.427","article-title":"Unique Cd8+ T cell-rich lymphoid aggregates in human uterine endometrium","volume":"61","author":"Yeaman","year":"1997","journal-title":"J Leukoc Biol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2567.2001.01199.x","article-title":"Cd8+ T cells in human uterine endometrial lymphoid aggregates: Evidence for accumulation of cells by trafficking","volume":"102","author":"Yeaman","year":"2001","journal-title":"Immunology"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1155\/DTE.3.127","article-title":"Lmmuno histochemical profile of endometrium in patients with genital endometriosis","volume":"3","author":"Mettler","year":"1997","journal-title":"Diagn Ther Endosc"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.humrep.a136286","article-title":"Bone marrow-derived cell populations in uterine and ectopic endometrium","volume":"10","author":"Fern\u00e1ndez-Shaw","year":"1995","journal-title":"Hum Reprod"},{"key":"B48","article-title":"[Peculiarities of immunocompetent cell distribution in the endometrium in the proliferation phase of the normal menstrual cycle]","author":"Dzhaparidze","year":"2006","journal-title":"Georgian Med News"},{"key":"B49","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1093\/humupd\/6.1.16","article-title":"Endometrial leukocytes and menstruation","volume":"6","author":"Salamonsen","year":"2000","journal-title":"Hum Reprod Update"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.765730","article-title":"The new old Cd8+ T cells in the immune paradox of pregnancy","volume":"12","author":"Hardardottir","year":"2021","journal-title":"Front Immunol"},{"key":"B51","doi-asserted-by":"crossref","first-page":"3017","DOI":"10.4049\/jimmunol.158.6.3017","article-title":"Cd3+ Cd8+ ctl activity within the human female reproductive tract: Influence of stage of the menstrual cycle and menopause","volume":"158","author":"White","year":"1997","journal-title":"J Immunol"},{"key":"B52","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.jri.2014.12.006","article-title":"The immune system in the normal endometrium and implications for endometrial cancer development","volume":"109","author":"Vanderstraeten","year":"2015","journal-title":"J Reprod Immunol"},{"key":"B53","volume-title":"Histology, T-cell lymphocyte","author":"Taylor.","year":"2022"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0897.2010.00852.x","article-title":"Th1\/Th2\/Th17 and regulatory T-cell paradigm in pregnancy","volume":"63","author":"Saito","year":"2010","journal-title":"Am J Reprod Immunol"},{"key":"B55","doi-asserted-by":"publisher","first-page":"2884","DOI":"10.1038\/s41598-017-03191-0","article-title":"Human uterine lymphocytes acquire a more experienced and tolerogenic phenotype during pregnancy","volume":"7","author":"Feyaerts","year":"2017","journal-title":"Sci Rep"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/deh159","article-title":"No difference in natural killer or natural killer T-cell population, but aberrant T-helper cell population in the endometrium of women with repeated miscarriage","volume":"19","author":"Shimada","year":"2004","journal-title":"Hum Reprod"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3298","article-title":"The burgeoning family of unconventional T cells","volume":"16","author":"Godfrey","year":"2015","journal-title":"Nat Immunol"},{"key":"B58","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1093\/humupd\/6.1.28","article-title":"Uterine leukocytes and decidualization","volume":"6","author":"King","year":"2000","journal-title":"Hum Reprod Update"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2004-1742","article-title":"Menstrual cycle hormones induce changes in functional interactions between lymphocytes and decidual vascular endothelial cells","volume":"90","author":"van den Heuvel","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1155\/1991\/83493","article-title":"Cd3- leukocytes present in the human uterus during early placentation: Phenotypic and morphologic characterization of the Cd56++ population","volume":"1","author":"King","year":"1991","journal-title":"Dev Immunol"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2008.03027.x","article-title":"Cd56bright natural killer (Nk) cells: An important nk cell subset","volume":"126","author":"Poli","year":"2009","journal-title":"Immunology"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.728291","article-title":"Role of decidual natural killer cells in human pregnancy and related pregnancy complications","volume":"12","author":"Zhang","year":"2021","journal-title":"Front Immunol"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1093\/hropen\/hoab043","article-title":"The role of endometrial b cells in normal endometrium and benign female reproductive pathologies: A systematic review","volume":"2022","author":"Shen","year":"2022","journal-title":"Hum Reprod Open"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2559.2004.02052.x","article-title":"Immunohistochemical characterization of endometrial leucocytes in endometritis","volume":"45","author":"Disep","year":"2004","journal-title":"Histopathology"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.709280","article-title":"B cell subset analysis and gene expression characterization in mid-luteal endometrium","volume":"9","author":"Shen","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0897.2012.01181.x","article-title":"A subset of human uterine endometrial macrophages is alternatively activated","volume":"68","author":"Jensen","year":"2012","journal-title":"Am J Reprod Immunol"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0105015","article-title":"Phenotypic and functional profiling of human proinflammatory type-1 and anti-inflammatory type-2 macrophages in response to microbial antigens and ifn-gamma- and Cd40l-mediated costimulation","volume":"79","author":"Verreck","year":"2006","journal-title":"J Leukoc Biol"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2009.03.022","article-title":"Presence of tumor-infiltrating lymphocytes is an independent prognostic factor in type I and ii endometrial cancer","volume":"114","author":"de Jong","year":"2009","journal-title":"Gynecol Oncol"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-0732-3","article-title":"Intratumoral Cd8+ T lymphocytes as a prognostic factor of survival in endometrial carcinoma","volume":"10","author":"Kondratiev","year":"2004","journal-title":"Clin Cancer Res"},{"key":"B70","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ejca.2016.02.026","article-title":"Cd103 defines intraepithelial Cd8+ Pd1+ tumour-infiltrating lymphocytes of prognostic significance in endometrial adenocarcinoma","volume":"60","author":"Workel","year":"2016","journal-title":"Eur J Cancer"},{"key":"B71","article-title":"Prognostic significance of Cd3+ tumor-infiltrating lymphocytes in patients with endometrial carcinoma","volume":"34","author":"\u010cerm\u00e1kov\u00e1","year":"2014","journal-title":"Anticancer Res"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2020.6371","article-title":"Tumor mutation burden and cancer treatment","volume":"7","author":"Fusco","year":"2021","journal-title":"JAMA Oncol"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.30496","article-title":"Confirmation of promise: A simple, genomics-based clinical classifier for endometrial cancer","volume":"123","author":"Talhouk","year":"2017","journal-title":"Cancer"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.Ccr-18-3241","article-title":"Molecular subtype not immune response drives outcomes in endometrial carcinoma","volume":"25","author":"Talhouk","year":"2019","journal-title":"Clin Cancer Res"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-003-0430-2","article-title":"B7-H1 pathway and its role in the evasion of tumor immunity","volume":"81","author":"Dong","year":"2003","journal-title":"J Mol Med"},{"key":"B76","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1146\/annurev.immunol.26.021607.090331","article-title":"Pd-1 and its ligands in tolerance and immunity","volume":"26","author":"Keir","year":"2008","journal-title":"Annu Rev Immunol"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-020-02813-3","article-title":"The immunologic tumor microenvironment in endometrioid endometrial cancer in the morphomolecular context: Mutual correlations and prognostic impact depending on molecular alterations","volume":"70","author":"Willvonseder","year":"2021","journal-title":"Cancer Immunol Immunother"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.640018","article-title":"Pole and mismatch repair status, checkpoint proteins and tumor-infiltrating lymphocytes in combination, and tumor differentiation: Identify endometrial cancers for immunotherapy","volume":"11","author":"Dong","year":"2021","journal-title":"Front Oncol"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-021-00930-7","article-title":"Prognostic implications of tumor-infiltrating T cells in early-stage endometrial cancer","volume":"35","author":"Mendiola","year":"2022","journal-title":"Modern Pathol"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-0620-x","article-title":"Pd-L1 engagement on T cells promotes self-tolerance and suppression of neighboring macrophages and effector T cells in cancer","volume":"21","author":"Diskin","year":"2020","journal-title":"Nat Immunol"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02368","article-title":"Tumor-infiltrating immune cells act as a marker for prognosis in colorectal cancer","volume":"10","author":"Ye","year":"2019","journal-title":"Front Immunol"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa020177","article-title":"Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer","volume":"348","author":"Zhang","year":"2003","journal-title":"N Engl J Med"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1002\/(sici)1097-0142(19960401)77:7<1303::Aid-cncr12>3.0.Co;2-5","article-title":"Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma","volume":"77","author":"Clemente","year":"1996","journal-title":"Cancer"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.554214","article-title":"Screening and identification of prognostic tumor-infiltrating immune cells and genes of endometrioid endometrial adenocarcinoma: Based on the cancer genome atlas database and bioinformatics","volume":"10","author":"Chen","year":"2020","journal-title":"Front Oncol"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00877","article-title":"Endometrial tumor microenvironment alters human nk cell recruitment, and resident nk cell phenotype and function","volume":"10","author":"Degos","year":"2019","journal-title":"Front Immunol"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-019-0760-3","article-title":"Tumor-associated macrophages in tumor metastasis: Biological roles and clinical therapeutic applications","volume":"12","author":"Lin","year":"2019","journal-title":"J Hematol Oncol"},{"key":"B87","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.cell.2010.03.014","article-title":"Macrophage diversity enhances tumor progression and metastasis","volume":"141","author":"Qian","year":"2010","journal-title":"Cell"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-022-00620-6","article-title":"Clinical relevance of tumour-associated macrophages","volume":"19","author":"Pittet","year":"2022","journal-title":"Nat Rev Clin Oncol"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1097\/PGP.0b013e318284e198","article-title":"Infiltration of tumor-associated macrophages is increased in the epithelial and stromal compartments of endometrial carcinomas","volume":"32","author":"Dun","year":"2013","journal-title":"Int J Gynecol Pathol"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1177\/1933719115570912","article-title":"Type 2 endometrial cancer is associated with a high density of tumor-associated macrophages in the stromal compartment","volume":"22","author":"Kelly","year":"2015","journal-title":"Reprod Sci"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/9731049","article-title":"Endometrial cancer cells promote M2-like macrophage polarization by delivering exosomal mirna-21 under hypoxia condition","volume":"2020","author":"Xiao","year":"2020","journal-title":"J Immunol Res"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.Can-21-2376","article-title":"Iga-dominated humoral immune responses govern patients' outcome in endometrial cancer","volume":"82","author":"Mandal","year":"2022","journal-title":"Cancer Res"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-021-03093-1","article-title":"Tertiary lymphoid structures are associated with favorable survival outcomes in patients with endometrial cancer","volume":"71","author":"Qin","year":"2022","journal-title":"Cancer Immunol Immunother"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.657326","article-title":"Endometrial cancer suppresses Cd8+ T cell-mediated cytotoxicity in postmenopausal women","volume":"12","author":"Patel","year":"2021","journal-title":"Front Immunol"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1097\/IGC.0b013e31822c271f","article-title":"Immunofluorescence-detected infiltration of Cd4+Foxp3+ regulatory T cells is relevant to the prognosis of patients with endometrial cancer","volume":"21","author":"Yamagami","year":"2011","journal-title":"Int J Gynecol Cancer"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1080\/2162402x.2019.1662708","article-title":"The role of myeloid-derived suppressor cells in endometrial cancer displaying systemic inflammatory response: Clinical and preclinical investigations","volume":"8","author":"Yokoi","year":"2019","journal-title":"Oncoimmunology"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmi046","article-title":"New progestagens for contraceptive use","volume":"12","author":"Sitruk-Ware","year":"2006","journal-title":"Hum Reprod Update"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1111\/aji.12535","article-title":"Effects of the levonorgestrel-releasing intrauterine device on the immune microenvironment of the human cervix and endometrium","volume":"76","author":"Shanmugasundaram","year":"2016","journal-title":"Am J Reprod Immunol"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1016\/j.contraception.2007.01.020","article-title":"Copper-T intrauterine device and levonorgestrel intrauterine system: Biological bases of their mechanism of action","volume":"75","author":"Ortiz","year":"2007","journal-title":"Contraception"},{"key":"B100","doi-asserted-by":"publisher","first-page":"6888","DOI":"10.1038\/s41598-020-63798-8","article-title":"Differential effects of the hormonal and copper intrauterine device on the endometrial transcriptome","volume":"10","author":"Smith-McCune","year":"2020","journal-title":"Sci Rep"},{"key":"B101","unstructured":"Obesity - overview2021"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.j477","article-title":"Adiposity and cancer at major anatomical sites: Umbrella review of the literature","volume":"356","author":"Kyrgiou","year":"2017","journal-title":"BMJ"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(14)60892-8","article-title":"Body-mass index and risk of 22 specific cancers: A population-based cohort study of 5\u00b724 million uk adults","volume":"384","author":"Bhaskaran","year":"2014","journal-title":"Lancet"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.69.4638","article-title":"Addressing the role of obesity in endometrial cancer risk, prevention, and treatment","volume":"34","author":"Onstad","year":"2016","journal-title":"J Clin Oncol Off J Am Soc Clin Oncol"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdv142","article-title":"Anthropometric factors and endometrial cancer risk: A systematic review and dose\u2013response meta-analysis of prospective studies","volume":"26","author":"Aune","year":"2015","journal-title":"Ann Oncol"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1111\/dom.14614","article-title":"Body mass index and cancer mortality in patients with incident type 2 diabetes: A population-based study of adults in England","volume":"24","author":"Alam","year":"2021","journal-title":"Diabetes Obes Metab"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1016\/j.soard.2014.09.024","article-title":"Bariatric surgery and risk of postoperative endometrial cancer: A systematic review and meta-analysis","volume":"11","author":"Upala","year":"2015","journal-title":"Surg Obes Relat Dis"},{"key":"B108","article-title":"Catch it before it kills: Progesterone, obesity, and the prevention of endometrial cancer","volume":"14","author":"Carlson","year":"2012","journal-title":"Discov Med"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.1155\/2010\/289645","article-title":"Chronic inflammation in obesity and the metabolic syndrome","author":"Monteiro","year":"2010","journal-title":"Mediators Inflammation"},{"key":"B110","doi-asserted-by":"publisher","DOI":"10.1038\/s41366-021-01027-6","article-title":"The impact of obesity and bariatric surgery on the immune microenvironment of the endometrium","volume":"46","author":"Naqvi","year":"2021","journal-title":"Int J Obes"},{"key":"B111","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1016\/j.metabol.2007.03.008","article-title":"Obesity and immune cell counts in women","volume":"56","author":"Womack","year":"2007","journal-title":"Metabolism"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-018-0251-7","article-title":"Metabolic reprogramming of natural killer cells in obesity limits antitumor responses","volume":"19","author":"Michelet","year":"2018","journal-title":"Nat Immunol"},{"key":"B113","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.85560","article-title":"Maternal obesity drives functional alterations in uterine nk cells","volume":"1","author":"Perdu","year":"2016","journal-title":"JCI Insight"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1089\/met.2018.0005","article-title":"Peripheral lymphocytes, obesity, and metabolic syndrome in young adults: An immunometabolism study","volume":"16","author":"Rodr\u00edguez","year":"2018","journal-title":"Metab Syndr Relat Disord"},{"key":"B115","doi-asserted-by":"publisher","DOI":"10.1002\/oby.21229","article-title":"Decreased nk cell functions in obesity can be reactivated by fat mass reduction","volume":"23","author":"Jahn","year":"2015","journal-title":"Obes (Silver Spring)"},{"key":"B116","doi-asserted-by":"publisher","first-page":"1848","DOI":"10.1016\/j.cell.2020.11.009","article-title":"Obesity shapes metabolism in the tumor microenvironment to suppress anti-tumor immunity","volume":"183","author":"Ringel","year":"2020","journal-title":"Cell"},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.15148","article-title":"No association of natural killer cell number and function in peripheral blood with Overweight\/Obesity and metabolic syndrome in a cohort of young women","volume":"10","author":"Keilen","year":"2022","journal-title":"Physiol Rep"},{"key":"B118","doi-asserted-by":"publisher","DOI":"10.3390\/biom11111700","article-title":"Overweight as a favorable clinical biomarker for checkpoint inhibitor therapy response in recurrent gynecologic cancer patients","volume":"11","author":"Bartl","year":"2021","journal-title":"Biomolecules"},{"key":"B119","doi-asserted-by":"publisher","DOI":"10.2174\/0929867327666200721160313","article-title":"Relationship between gut microbiota, gut hyperpermeability and obesity","volume":"28","author":"Gasmi","year":"2021","journal-title":"Curr Med Chem"},{"key":"B120","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2020-321153","article-title":"The role of gut microbiota in cancer treatment: Friend or foe","volume":"69","author":"Cheng","year":"2020","journal-title":"Gut"},{"key":"B121","doi-asserted-by":"publisher","DOI":"10.4172\/2155-9929.1000350","article-title":"Cancer immunotherapy and personalized medicine: Emerging technologies and biomarker-based approaches","volume":"8","author":"Maciejko","year":"2017","journal-title":"J Mol biomark Diagn"},{"key":"B122","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.Ccr-19-2309","article-title":"Mutation-derived neoantigen-specific T-cell responses in multiple myeloma","volume":"26","author":"Perumal","year":"2020","journal-title":"Clin Cancer Res"},{"key":"B123","doi-asserted-by":"publisher","DOI":"10.1200\/edbk_280503","article-title":"A review of immune checkpoint blockade therapy in endometrial cancer","author":"Green","year":"2020","journal-title":"Am Soc Clin Oncol Educ Book"},{"key":"B124","doi-asserted-by":"publisher","DOI":"10.3802\/jgo.2019.30.e46","article-title":"Immunotherapy in endometrial cancer: New scenarios on the horizon","volume":"30","author":"Di Tucci","year":"2019","journal-title":"J Gynecol Oncol"},{"key":"B125","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9061721","article-title":"Immune checkpoint inhibitors: A promising choice for endometrial cancer patients","volume":"9","author":"Musacchio","year":"2020","journal-title":"J Clin Med"},{"key":"B126","doi-asserted-by":"publisher","DOI":"10.1007\/s00404-019-05372-w","article-title":"Prognostic values of pretreatment neutrophil-to-Lymphocyte and platelet-to-Lymphocyte ratios in endometrial cancer: A systematic review and meta-analysis","volume":"301","author":"Ni","year":"2020","journal-title":"Arch Gynecol Obstet"},{"key":"B127","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2020.11774","article-title":"Immune disorder in endometrial cancer: Immunosuppressive microenvironment, mechanisms of immune evasion and immunotherapy","volume":"20","author":"Zhan","year":"2020","journal-title":"Oncol Lett"},{"key":"B128","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2016.04.002","article-title":"The significance and therapeutic potential of pd-1 and its ligands in ovarian cancer: A systematic review","volume":"142","author":"Zhu","year":"2016","journal-title":"Gynecol Oncol"},{"key":"B129","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3239","article-title":"The blockade of immune checkpoints in cancer immunotherapy","volume":"12","author":"Pardoll","year":"2012","journal-title":"Nat Rev Cancer"},{"key":"B130","doi-asserted-by":"publisher","DOI":"10.1136\/esmoopen-2019-000497","article-title":"New emerging targets in cancer immunotherapy: The role of Tim3","volume":"4","author":"Friedlaender","year":"2019","journal-title":"ESMO Open"},{"key":"B131","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2017.72.5952","article-title":"Safety and antitumor activity of pembrolizumab in advanced programmed death ligand 1\u2013positive endometrial cancer: Results from the keynote-028 study","volume":"35","author":"Ott","year":"2017","journal-title":"J Clin Oncol"},{"key":"B132","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2201445","article-title":"Pd-1 blockade in mismatch repair-deficient, locally advanced rectal cancer","volume":"386","author":"Cercek","year":"2022","journal-title":"N Engl J Med"},{"key":"B133","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbaa180","article-title":"Microsatellite instability status differentially associates with intratumoral immune microenvironment in human cancers","volume":"22","author":"Zhang","year":"2021","journal-title":"Brief Bioinform"},{"key":"B134","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-020-00682-w","article-title":"Mhc class I loss in endometrial carcinoma: A potential resistance mechanism to immune checkpoint inhibition","volume":"34","author":"Friedman","year":"2021","journal-title":"Mod Pathol"},{"key":"B135","doi-asserted-by":"publisher","DOI":"10.2147\/OTT.S170385","article-title":"Tim-3, a promising target for cancer immunotherapy","volume":"11","author":"He","year":"2018","journal-title":"OncoTargets Ther"},{"key":"B136","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-019-0251-7","article-title":"Tim-3 in endometrial carcinomas: An immunotherapeutic target expressed by mismatch repair-deficient and intact cancers","volume":"32","author":"Moore","year":"2019","journal-title":"Mod Pathol"},{"key":"B137","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2020.100918","article-title":"Tim3 expression on tumor cells predicts response to anti-Pd-1 therapy for renal cancer","volume":"14","author":"Kato","year":"2021","journal-title":"Transl Oncol"},{"key":"B138","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.Ccr-21-0261","article-title":"Safety and antitumor activity of \u03b1-Pd-L1 antibody as monotherapy or in combination with \u03b1-Tim-3 antibody in patients with microsatellite instability-High\/Mismatch repair-deficient tumors","volume":"27","author":"Hollebecque","year":"2021","journal-title":"Clin Cancer Res"},{"key":"B139","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/6156757","article-title":"Cd47 blockade inhibits tumor progression through promoting phagocytosis of tumor cells by M2 polarized macrophages in endometrial cancer","volume":"2018","author":"Gu","year":"2018","journal-title":"J Immunol Res"},{"key":"B140","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2012.00191","article-title":"Radiation-induced effects and the immune system in cancer","volume":"2","author":"Kaur","year":"2012","journal-title":"Front Oncol"},{"key":"B141","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04522-6","article-title":"Androgen receptor activity in T cells limits checkpoint blockade efficacy","volume":"606","author":"Guan","year":"2022","journal-title":"Nature"},{"key":"B142","doi-asserted-by":"publisher","DOI":"10.1016\/j.semradonc.2014.07.005","article-title":"Radiotherapy and immunogenic cell death","volume":"25","author":"Golden","year":"2015","journal-title":"Semin Radiat Oncol"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.975201\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,15]],"date-time":"2023-02-15T07:46:33Z","timestamp":1676447193000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.975201\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,22]]},"references-count":142,"alternative-id":["10.3389\/fonc.2022.975201"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2022.975201","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,22]]},"article-number":"975201"}}