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Immune checkpoint inhibitors (ICIs) used in cancer immunotherapy allow T-cell activation against cancer cells. Retrospective studies showed increased VTE following ICI administration in some patients. Non-small cell lung cancer (NSCLC) patients are at high risk of thrombosis and thus, the adoption of immunotherapy, as a first-line treatment, seems to be associated with coagulation-fibrinolysis derangement. Methods: We pharmacologically modulated NSCLC cell lines in co-culture with CD8+ T-cells (TCD8+) and myeloid-derived suppressor cells (MDSCs), isolated from healthy blood donors. The effects of ICIs Nivolumab and Ipilimumab on NSCLC cell death were assessed by annexin V and propidium iodide (PI) flow cytometry analysis. The potential procoagulant properties were analyzed by in vitro clotting assays and enzyme-linked immunosorbent assays (ELISAs). The metabolic remodeling induced by the ICIs was explored by 1H nuclear magnetic resonance (NMR) spectroscopy. Results: Flow cytometry analysis showed that TCD8+ and ICIs increase cell death in H292 and PC-9 cells but not in A549 cells. Conditioned media from NSCLC cells exposed to TCD8+ and ICI induced in vitro platelet aggregation. In A549, Podoplanin (PDPN) levels increased with Nivolumab. In H292, ICIs increased PDPN levels in the absence of TCD8+. In PC-9, Ipilimumab decreased PDPN levels, this effect being rescued by TCD8+. MDSCs did not interfere with the effect of TCD8+ in the production of TF or PDPN in any NSCLC cell lines. The exometabolome showed a metabolic remodeling in NSCLC cells upon exposure to TCD8+ and ICIs. Conclusions: This study provides some insights into the interplay of immune cells, ICIs and cancer cells influencing the coagulation status. ICIs are important promoters of coagulation, benefiting from TCD8+ mediation. The exometabolome analysis highlighted the relevance of acetate, pyruvate, glycine, glutamine, valine, leucine and isoleucine as biomarkers. Further investigation is needed to validate this finding in a cohort of NSCLC patients.<\/jats:p>","DOI":"10.3390\/cells13040305","type":"journal-article","created":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T03:47:09Z","timestamp":1707277629000},"page":"305","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Interaction between NSCLC Cells, CD8+ T-Cells and Immune Checkpoint Inhibitors Potentiates Coagulation and Promotes Metabolic Remodeling\u2014New Cues on CAT-VTE"],"prefix":"10.3390","volume":"13","author":[{"given":"Catarina","family":"Freitas-Dias","sequence":"first","affiliation":[{"name":"iNOVA4Health, NOVA Medical School, Faculdade de Ci\u00eancias M\u00e9dicas, NMS, FCM, Universidade NOVA de Lisboa, Campo dos M\u00e1rtires da P\u00e1tria, 130, 1169-056 Lisboa, Portugal"},{"name":"Instituto Portugu\u00eas de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisboa, Portugal"},{"name":"Faculdade de Ci\u00eancias, FCUL, Universidade de Lisboa, Campo Grande, 130, 1169-056 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0582-137X","authenticated-orcid":false,"given":"Filipe","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"iNOVA4Health, NOVA Medical School, Faculdade de Ci\u00eancias M\u00e9dicas, NMS, FCM, Universidade NOVA de Lisboa, Campo dos M\u00e1rtires da P\u00e1tria, 130, 1169-056 Lisboa, Portugal"},{"name":"Instituto Portugu\u00eas de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7869-7173","authenticated-orcid":false,"given":"Filipa","family":"Martins","sequence":"additional","affiliation":[{"name":"iNOVA4Health, NOVA Medical School, Faculdade de Ci\u00eancias M\u00e9dicas, NMS, FCM, Universidade NOVA de Lisboa, Campo dos M\u00e1rtires da P\u00e1tria, 130, 1169-056 Lisboa, Portugal"},{"name":"Instituto Portugu\u00eas de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisboa, Portugal"}]},{"given":"Isabel","family":"Lemos","sequence":"additional","affiliation":[{"name":"iNOVA4Health, NOVA Medical School, Faculdade de Ci\u00eancias M\u00e9dicas, NMS, FCM, Universidade NOVA de Lisboa, Campo dos M\u00e1rtires da P\u00e1tria, 130, 1169-056 Lisboa, Portugal"},{"name":"Instituto Portugu\u00eas de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5683-3552","authenticated-orcid":false,"given":"Lu\u00eds G.","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier (ITQB NOVA), Avenida da Rep\u00fablica (EAN), 2780-157 Oeiras, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1548-5907","authenticated-orcid":false,"given":"Jacinta","family":"Serpa","sequence":"additional","affiliation":[{"name":"iNOVA4Health, NOVA Medical School, Faculdade de Ci\u00eancias M\u00e9dicas, NMS, FCM, Universidade NOVA de Lisboa, Campo dos M\u00e1rtires da P\u00e1tria, 130, 1169-056 Lisboa, Portugal"},{"name":"Instituto Portugu\u00eas de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.bbcan.2015.08.002","article-title":"Lung cancer: Biology and treatment options","volume":"1856","author":"Hassan","year":"2015","journal-title":"Biochim. 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