{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T18:09:55Z","timestamp":1787508595792,"version":"build-2736575974"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2022,11,27]],"date-time":"2022-11-27T00:00:00Z","timestamp":1669507200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,11,27]],"date-time":"2022-11-27T00:00:00Z","timestamp":1669507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cancer Immunol Immunother"],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    A variety of variables, such as microsatellite instability or inflammatory mediators, are critical players in the development and progression of colorectal cancer (CRC). Natural killer (NK) and natural killer T (NKT) cells are involved in the prognoses of CRC. Immunological components of the tumor microenvironment (TME) impact cancer progression and therapeutic responses. We report that CRC patients with higher frequencies of tumor-infiltrating PD-1\n                    <jats:sup>+<\/jats:sup>\n                    NK and NKT cells had significantly longer disease-free survival (DFS) than patients with lower frequencies. In agreement with that, patients with higher frequencies of tumor-infiltrating PD-1\n                    <jats:sup>\u2212<\/jats:sup>\n                    NK and NKT cells showed shorter DFS. There were no significant associations between tumor-infiltrating PD-1\n                    <jats:sup>+<\/jats:sup>\n                    TIM-3\n                    <jats:sup>+<\/jats:sup>\n                    , PD-1\n                    <jats:sup>+<\/jats:sup>\n                    TIGIT\n                    <jats:sup>+<\/jats:sup>\n                    , PD-1\n                    <jats:sup>+<\/jats:sup>\n                    ICOS\n                    <jats:sup>+<\/jats:sup>\n                    , PD-1\n                    <jats:sup>+<\/jats:sup>\n                    LAG-3\n                    <jats:sup>+<\/jats:sup>\n                    NK cells, and PD-1\n                    <jats:sup>+<\/jats:sup>\n                    TIM-3\n                    <jats:sup>+<\/jats:sup>\n                    , PD-1\n                    <jats:sup>+<\/jats:sup>\n                    TIGIT\n                    <jats:sup>+<\/jats:sup>\n                    , and PD-1\n                    <jats:sup>+<\/jats:sup>\n                    LAG-3\n                    <jats:sup>+<\/jats:sup>\n                    NKT cells with DFS. This study highlights the significance of PD-1 expression on tumor-infiltrating NK and NKT cells and its association with disease prognoses in CRC patients.\n                  <\/jats:p>","DOI":"10.1007\/s00262-022-03337-8","type":"journal-article","created":{"date-parts":[[2022,11,27]],"date-time":"2022-11-27T06:30:13Z","timestamp":1669530613000},"page":"1933-1939","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["PD-1 expression, among other immune checkpoints, on tumor-infiltrating NK and NKT cells is associated with longer disease-free survival in treatment-na\u00efve CRC patients"],"prefix":"10.1007","volume":"72","author":[{"given":"Mohammad A.","family":"Al-Mterin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khaled","family":"Murshed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eyad","family":"Elkord","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,11,27]]},"reference":[{"issue":"6","key":"3337_CR1","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3322\/caac.21492","volume":"68","author":"F Bray","year":"2018","unstructured":"Bray F et al (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394\u2013424","journal-title":"CA Cancer J Clin"},{"issue":"10","key":"3337_CR2","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1038\/nri3896","volume":"15","author":"NR West","year":"2015","unstructured":"West NR et al (2015) Emerging cytokine networks in colorectal cancer. Nat Rev Immunol 15(10):615\u2013629","journal-title":"Nat Rev Immunol"},{"issue":"25","key":"3337_CR3","doi-asserted-by":"publisher","first-page":"3937","DOI":"10.3748\/wjg.14.3937","volume":"14","author":"PL Lakatos","year":"2008","unstructured":"Lakatos PL, Lakatos L (2008) Risk for colorectal cancer in ulcerative colitis: changes, causes and management strategies. World J Gastroenterol 14(25):3937\u20133947","journal-title":"World J Gastroenterol"},{"issue":"19\u201320","key":"3337_CR4","doi-asserted-by":"publisher","first-page":"1267","DOI":"10.1101\/gad.314617.118","volume":"32","author":"H Gonzalez","year":"2018","unstructured":"Gonzalez H, Hagerling C, Werb Z (2018) Roles of the immune system in cancer: from tumor initiation to metastatic progression. Genes Dev 32(19\u201320):1267\u20131284","journal-title":"Genes Dev"},{"issue":"2","key":"3337_CR5","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1038\/nri.2015.9","volume":"16","author":"A Cerwenka","year":"2016","unstructured":"Cerwenka A, Lanier LL (2016) Natural killer cell memory in infection, inflammation and cancer. Nat Rev Immunol 16(2):112\u2013123","journal-title":"Nat Rev Immunol"},{"key":"3337_CR6","doi-asserted-by":"publisher","first-page":"18","DOI":"10.3389\/fimmu.2011.00018","volume":"2","author":"E Vivier","year":"2011","unstructured":"Vivier E, Ugolini S (2011) Natural killer cells: from basic research to treatments. Front Immunol 2:18","journal-title":"Front Immunol"},{"issue":"1","key":"3337_CR7","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/s12876-020-1177-8","volume":"20","author":"YP Tang","year":"2020","unstructured":"Tang YP et al (2020) Prognostic value of peripheral blood natural killer cells in colorectal cancer. BMC Gastroenterol 20(1):31","journal-title":"BMC Gastroenterol"},{"issue":"4","key":"3337_CR8","doi-asserted-by":"publisher","first-page":"980","DOI":"10.1053\/j.gastro.2017.06.009","volume":"153","author":"G Jobin","year":"2017","unstructured":"Jobin G, Rodriguez-Suarez R, Betito K (2017) Association between natural killer cell activity and colorectal cancer in high-risk subjects undergoing colonoscopy. Gastroenterology 153(4):980\u2013987","journal-title":"Gastroenterology"},{"key":"3337_CR9","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1016\/j.molimm.2020.10.012","volume":"128","author":"D Krijgsman","year":"2020","unstructured":"Krijgsman D et al (2020) Expression of NK cell receptor ligands in primary colorectal cancer tissue in relation to the phenotype of circulating NK- and NKT cells, and clinical outcome. Mol Immunol 128:205\u2013218","journal-title":"Mol Immunol"},{"key":"3337_CR10","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1146\/annurev.immunol.25.022106.141711","volume":"25","author":"A Bendelac","year":"2007","unstructured":"Bendelac A, Savage PB, Teyton L (2007) The biology of NKT cells. Annu Rev Immunol 25:297\u2013336","journal-title":"Annu Rev Immunol"},{"key":"3337_CR11","doi-asserted-by":"publisher","first-page":"367","DOI":"10.3389\/fimmu.2018.00367","volume":"9","author":"D Krijgsman","year":"2018","unstructured":"Krijgsman D, Hokland M, Kuppen PJK (2018) The role of natural killer T cells in cancer\u2014a phenotypical and functional approach. Front Immunol 9:367","journal-title":"Front Immunol"},{"key":"3337_CR12","doi-asserted-by":"publisher","first-page":"2936","DOI":"10.3389\/fimmu.2019.02936","volume":"10","author":"SM Toor","year":"2019","unstructured":"Toor SM et al (2019) Immune checkpoints in circulating and tumor-infiltrating CD4(+) T Cell subsets in colorectal cancer patients. Front Immunol 10:2936","journal-title":"Front Immunol"},{"issue":"1","key":"3337_CR13","doi-asserted-by":"publisher","first-page":"64","DOI":"10.3390\/vaccines9010064","volume":"9","author":"SM Toor","year":"2021","unstructured":"Toor SM et al (2021) Tumor-infiltrating lymphoid cells in colorectal cancer patients with varying disease stages and microsatellite instability-high\/stable tumors. Vaccines (Basel) 9(1):64","journal-title":"Vaccines (Basel)"},{"issue":"8","key":"3337_CR14","doi-asserted-by":"publisher","first-page":"1230","DOI":"10.1158\/2326-6066.CIR-18-0683","volume":"7","author":"C Gurjao","year":"2019","unstructured":"Gurjao C et al (2019) Intrinsic resistance to immune checkpoint blockade in a mismatch repair-deficient colorectal cancer. Cancer Immunol Res 7(8):1230\u20131236","journal-title":"Cancer Immunol Res"},{"issue":"19","key":"3337_CR15","doi-asserted-by":"publisher","first-page":"5217","DOI":"10.1158\/1078-0432.CCR-20-0558","volume":"26","author":"ZZ Yang","year":"2020","unstructured":"Yang ZZ et al (2020) TIGIT expression is associated with T-cell suppression and exhaustion and predicts clinical outcome and anti-PD-1 response in follicular lymphoma. Clin Cancer Res 26(19):5217\u20135231","journal-title":"Clin Cancer Res"},{"issue":"1","key":"3337_CR16","doi-asserted-by":"publisher","first-page":"1905935","DOI":"10.1080\/2162402X.2021.1905935","volume":"10","author":"P Maby","year":"2021","unstructured":"Maby P et al (2021) License to kill: microsatellite instability and immune contexture. Oncoimmunology 10(1):1905935","journal-title":"Oncoimmunology"},{"key":"3337_CR17","doi-asserted-by":"publisher","first-page":"2039","DOI":"10.3389\/fimmu.2020.02039","volume":"11","author":"A Lin","year":"2020","unstructured":"Lin A, Zhang J, Luo P (2020) Crosstalk between the MSI status and tumor microenvironment in colorectal cancer. Front Immunol 11:2039","journal-title":"Front Immunol"},{"issue":"1","key":"3337_CR18","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1186\/s13045-021-01166-3","volume":"14","author":"W Wu","year":"2021","unstructured":"Wu W et al (2021) Intratumor heterogeneity: the hidden barrier to immunotherapy against MSI tumors from the perspective of IFN-\u03b3 signaling and tumor-infiltrating lymphocytes. J Hematol Oncol 14(1):160","journal-title":"J Hematol Oncol"},{"issue":"15","key":"3337_CR19","doi-asserted-by":"publisher","first-page":"2788","DOI":"10.1016\/j.ejca.2010.05.009","volume":"46","author":"C Guastadisegni","year":"2010","unstructured":"Guastadisegni C et al (2010) Microsatellite instability as a marker of prognosis and response to therapy: a meta-analysis of colorectal cancer survival data. Eur J Cancer 46(15):2788\u20132798","journal-title":"Eur J Cancer"},{"issue":"3","key":"3337_CR20","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1200\/JCO.2005.01.086","volume":"23","author":"S Popat","year":"2005","unstructured":"Popat S, Hubner R, Houlston RS (2005) Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 23(3):609\u2013618","journal-title":"J Clin Oncol"},{"issue":"1","key":"3337_CR21","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1186\/s12957-019-1706-5","volume":"17","author":"B Wang","year":"2019","unstructured":"Wang B et al (2019) Is microsatellite instability-high really a favorable prognostic factor for advanced colorectal cancer? A meta-analysis. World J Surg Oncol 17(1):169","journal-title":"World J Surg Oncol"},{"key":"3337_CR22","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.smim.2017.08.003","volume":"31","author":"L Chiossone","year":"2017","unstructured":"Chiossone L et al (2017) Natural killer cell immunotherapies against cancer: checkpoint inhibitors and more. Semin Immunol 31:55\u201363","journal-title":"Semin Immunol"},{"issue":"1","key":"3337_CR23","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1016\/j.jaci.2016.04.025","volume":"139","author":"S Pesce","year":"2017","unstructured":"Pesce S et al (2017) Identification of a subset of human natural killer cells expressing high levels of programmed death 1: a phenotypic and functional characterization. J Allergy Clin Immunol 139(1):335-346.e3","journal-title":"J Allergy Clin Immunol"},{"issue":"10","key":"3337_CR24","doi-asserted-by":"publisher","first-page":"2187","DOI":"10.1084\/jem.20100643","volume":"207","author":"K Sakuishi","year":"2010","unstructured":"Sakuishi K et al (2010) Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med 207(10):2187\u20132194","journal-title":"J Exp Med"},{"issue":"8","key":"3337_CR25","doi-asserted-by":"publisher","first-page":"1505","DOI":"10.1007\/s00262-020-02558-z","volume":"69","author":"MP Trefny","year":"2020","unstructured":"Trefny MP et al (2020) PD-1(+) natural killer cells in human non-small cell lung cancer can be activated by PD-1\/PD-L1 blockade. Cancer Immunol Immunother 69(8):1505\u20131517","journal-title":"Cancer Immunol Immunother"},{"issue":"13","key":"3337_CR26","doi-asserted-by":"publisher","first-page":"2889","DOI":"10.1111\/bph.15081","volume":"177","author":"FR Mariotti","year":"2020","unstructured":"Mariotti FR et al (2020) Inhibitory checkpoints in human natural killer cells: IUPHAR review 28. Br J Pharmacol 177(13):2889\u20132903","journal-title":"Br J Pharmacol"},{"issue":"13","key":"3337_CR27","doi-asserted-by":"publisher","first-page":"2286","DOI":"10.1182\/blood-2010-02-271874","volume":"116","author":"DM Benson Jr","year":"2010","unstructured":"Benson DM Jr et al (2010) The PD-1\/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood 116(13):2286\u20132294","journal-title":"Blood"},{"issue":"4","key":"3337_CR28","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1158\/2326-6066.CIR-13-0133","volume":"2","author":"AW MacFarlane","year":"2014","unstructured":"MacFarlane AW et al (2014) PD-1 expression on peripheral blood cells increases with stage in renal cell carcinoma patients and is rapidly reduced after surgical tumor resection. Cancer Immunol Res 2(4):320\u2013331","journal-title":"Cancer Immunol Res"},{"issue":"16","key":"3337_CR29","doi-asserted-by":"publisher","first-page":"1809","DOI":"10.1182\/blood-2017-07-796342","volume":"131","author":"F Vari","year":"2018","unstructured":"Vari F et al (2018) Immune evasion via PD-1\/PD-L1 on NK cells and monocyte\/macrophages is more prominent in Hodgkin lymphoma than DLBCL. Blood 131(16):1809\u20131819","journal-title":"Blood"},{"issue":"44","key":"3337_CR30","doi-asserted-by":"publisher","first-page":"6143","DOI":"10.1038\/onc.2017.209","volume":"36","author":"Y Liu","year":"2017","unstructured":"Liu Y et al (2017) Increased expression of programmed cell death protein 1 on NK cells inhibits NK-cell-mediated anti-tumor function and indicates poor prognosis in digestive cancers. Oncogene 36(44):6143\u20136153","journal-title":"Oncogene"},{"issue":"4","key":"3337_CR31","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1016\/j.cell.2020.01.022","volume":"180","author":"P Dogra","year":"2020","unstructured":"Dogra P et al (2020) Tissue determinants of human NK cell development, function, and residence. Cell 180(4):749-763.e13","journal-title":"Cell"},{"issue":"10","key":"3337_CR32","doi-asserted-by":"publisher","first-page":"6707","DOI":"10.4049\/jimmunol.181.10.6707","volume":"181","author":"WS Chang","year":"2008","unstructured":"Chang WS et al (2008) Cutting edge: programmed death-1\/programmed death ligand 1 interaction regulates the induction and maintenance of invariant NKT cell anergy. J Immunol 181(10):6707\u20136710","journal-title":"J Immunol"},{"issue":"12","key":"3337_CR33","doi-asserted-by":"publisher","first-page":"1477","DOI":"10.1007\/s00262-016-1901-y","volume":"65","author":"T Kamata","year":"2016","unstructured":"Kamata T et al (2016) Blockade of programmed death-1\/programmed death ligand pathway enhances the antitumor immunity of human invariant natural killer T cells. Cancer Immunol Immunother 65(12):1477\u20131489","journal-title":"Cancer Immunol Immunother"},{"issue":"4","key":"3337_CR34","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1007\/s00262-010-0963-5","volume":"60","author":"K Durgan","year":"2011","unstructured":"Durgan K et al (2011) Targeting NKT cells and PD-L1 pathway results in augmented anti-tumor responses in a melanoma model. Cancer Immunol Immunother 60(4):547\u2013558","journal-title":"Cancer Immunol Immunother"},{"issue":"15","key":"3337_CR35","doi-asserted-by":"publisher","first-page":"4663","DOI":"10.1158\/1078-0432.CCR-18-4142","volume":"25","author":"I Datar","year":"2019","unstructured":"Datar I et al (2019) Expression analysis and significance of PD-1, LAG-3, and TIM-3 in human non-small cell lung cancer using spatially resolved and multiparametric single-cell analysis. Clin Cancer Res 25(15):4663\u20134673","journal-title":"Clin Cancer Res"},{"issue":"4","key":"3337_CR36","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1111\/imm.12098","volume":"139","author":"NK Bj\u00f6rkstr\u00f6m","year":"2013","unstructured":"Bj\u00f6rkstr\u00f6m NK, Kek\u00e4l\u00e4inen E, Mj\u00f6sberg J (2013) Tissue-specific effector functions of innate lymphoid cells. Immunology 139(4):416\u2013427","journal-title":"Immunology"}],"container-title":["Cancer Immunology, Immunotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00262-022-03337-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00262-022-03337-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00262-022-03337-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,19]],"date-time":"2023-05-19T11:02:03Z","timestamp":1684494123000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00262-022-03337-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,27]]},"references-count":36,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2023,6]]}},"alternative-id":["3337"],"URL":"https:\/\/doi.org\/10.1007\/s00262-022-03337-8","relation":{},"ISSN":["0340-7004","1432-0851"],"issn-type":[{"value":"0340-7004","type":"print"},{"value":"1432-0851","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,27]]},"assertion":[{"value":"25 September 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 November 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 November 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of the Medical Research Center, Hamad Medical Corporation (protocol no. MRC-02-18-012).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Informed consent for publication was obtained from all subjects involved in the study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}]}}