Effects of a Novel Thiadiazole Derivative with High Anticancer Activity on Cancer Cell Immunogenic Markers: Mismatch Repair System, PD-L1 Expression, and Tumor Mutation Burden
Microsatellite instability (MSI), tumor mutation burden (TMB), and programmed cell death ligand-1 (PD-L1) are particularly known as immunotherapy predictive biomarkers. MSI and TMB are closely related to DNA mismatch repair (MMR) pathway functionality, while the PD-L1 checkpoint mediates cancer cell...
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MDPI AG
2021-06-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/13/6/885 |
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| author | Sofia Sagredou Panagiotis Dalezis Eirini Papadopoulou Maria Voura Maria V. Deligiorgi Michail Nikolaou Mihalis I. Panayiotidis George Nasioulas Vasiliki Sarli Dimitrios T. Trafalis |
| author_facet | Sofia Sagredou Panagiotis Dalezis Eirini Papadopoulou Maria Voura Maria V. Deligiorgi Michail Nikolaou Mihalis I. Panayiotidis George Nasioulas Vasiliki Sarli Dimitrios T. Trafalis |
| author_sort | Sofia Sagredou |
| collection | DOAJ |
| description | Microsatellite instability (MSI), tumor mutation burden (TMB), and programmed cell death ligand-1 (PD-L1) are particularly known as immunotherapy predictive biomarkers. MSI and TMB are closely related to DNA mismatch repair (MMR) pathway functionality, while the PD-L1 checkpoint mediates cancer cell evasion from immune surveillance via the PD-L1/PD-1 axis. Among all the novel triazolo[3,4-<i>b</i>]thiadiazole derivatives, the compound KA39 emerged as the most potent anticancer agent. In the present study, potential alterations in MSI, TMB, and/or PD-L1 expression upon cell treatment with KA39 are explored. We tested three MMR-deficient (DLD-1, LS174T, and DU-145) and two MMR-proficient (HT-29 and PC-3) human cancer cell lines. Our findings support KA39-induced PD-L1 overexpression in all cancer cell lines, although the most outstanding increase was observed in MMR-proficient HT-29 cells. MSI analysis showed that KA39 affects the MMR system, impairing its recognition or repair activity, particularly in MMR-deficient DLD-1 and DU-145 cells, enhancing oligonucleotide production. There were no remarkable alterations in the TMB between untreated and treated cells, indicating that KA39 does not belong to mutagenic agents. Taking together the significant in vitro anticancer activity with PD-L1 upregulation and MSI increase, KA39 should be investigated further for its implication in chemo-immunotherapy of cancer. |
| first_indexed | 2024-03-10T10:24:49Z |
| format | Article |
| id | doaj.art-ce2ff20c49d5441983f74106e6faecb7 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T10:24:49Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-ce2ff20c49d5441983f74106e6faecb72023-11-22T00:10:27ZengMDPI AGPharmaceutics1999-49232021-06-0113688510.3390/pharmaceutics13060885Effects of a Novel Thiadiazole Derivative with High Anticancer Activity on Cancer Cell Immunogenic Markers: Mismatch Repair System, PD-L1 Expression, and Tumor Mutation BurdenSofia Sagredou0Panagiotis Dalezis1Eirini Papadopoulou2Maria Voura3Maria V. Deligiorgi4Michail Nikolaou5Mihalis I. Panayiotidis6George Nasioulas7Vasiliki Sarli8Dimitrios T. Trafalis9Laboratory of Pharmacology, Medical School, National & Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Athens, GreeceLaboratory of Pharmacology, Medical School, National & Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Athens, GreeceGenekor Medical, Spaton 52, Ave., 15344 Athens, GreeceDepartment of Chemistry, Aristotle University of Thessaloniki, University Campus, 54124 Thessaloniki, GreeceLaboratory of Pharmacology, Medical School, National & Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Athens, GreeceLaboratory of Pharmacology, Medical School, National & Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Athens, GreeceDepartment of Electron Microscopy & Molecular Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, CyprusGenekor Medical, Spaton 52, Ave., 15344 Athens, GreeceDepartment of Chemistry, Aristotle University of Thessaloniki, University Campus, 54124 Thessaloniki, GreeceLaboratory of Pharmacology, Medical School, National & Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Athens, GreeceMicrosatellite instability (MSI), tumor mutation burden (TMB), and programmed cell death ligand-1 (PD-L1) are particularly known as immunotherapy predictive biomarkers. MSI and TMB are closely related to DNA mismatch repair (MMR) pathway functionality, while the PD-L1 checkpoint mediates cancer cell evasion from immune surveillance via the PD-L1/PD-1 axis. Among all the novel triazolo[3,4-<i>b</i>]thiadiazole derivatives, the compound KA39 emerged as the most potent anticancer agent. In the present study, potential alterations in MSI, TMB, and/or PD-L1 expression upon cell treatment with KA39 are explored. We tested three MMR-deficient (DLD-1, LS174T, and DU-145) and two MMR-proficient (HT-29 and PC-3) human cancer cell lines. Our findings support KA39-induced PD-L1 overexpression in all cancer cell lines, although the most outstanding increase was observed in MMR-proficient HT-29 cells. MSI analysis showed that KA39 affects the MMR system, impairing its recognition or repair activity, particularly in MMR-deficient DLD-1 and DU-145 cells, enhancing oligonucleotide production. There were no remarkable alterations in the TMB between untreated and treated cells, indicating that KA39 does not belong to mutagenic agents. Taking together the significant in vitro anticancer activity with PD-L1 upregulation and MSI increase, KA39 should be investigated further for its implication in chemo-immunotherapy of cancer.https://www.mdpi.com/1999-4923/13/6/885thiadiazole derivativecancer immunogenic markersMMR impairmentPD-L1 upregulationtumor mutation burden |
| spellingShingle | Sofia Sagredou Panagiotis Dalezis Eirini Papadopoulou Maria Voura Maria V. Deligiorgi Michail Nikolaou Mihalis I. Panayiotidis George Nasioulas Vasiliki Sarli Dimitrios T. Trafalis Effects of a Novel Thiadiazole Derivative with High Anticancer Activity on Cancer Cell Immunogenic Markers: Mismatch Repair System, PD-L1 Expression, and Tumor Mutation Burden Pharmaceutics thiadiazole derivative cancer immunogenic markers MMR impairment PD-L1 upregulation tumor mutation burden |
| title | Effects of a Novel Thiadiazole Derivative with High Anticancer Activity on Cancer Cell Immunogenic Markers: Mismatch Repair System, PD-L1 Expression, and Tumor Mutation Burden |
| title_full | Effects of a Novel Thiadiazole Derivative with High Anticancer Activity on Cancer Cell Immunogenic Markers: Mismatch Repair System, PD-L1 Expression, and Tumor Mutation Burden |
| title_fullStr | Effects of a Novel Thiadiazole Derivative with High Anticancer Activity on Cancer Cell Immunogenic Markers: Mismatch Repair System, PD-L1 Expression, and Tumor Mutation Burden |
| title_full_unstemmed | Effects of a Novel Thiadiazole Derivative with High Anticancer Activity on Cancer Cell Immunogenic Markers: Mismatch Repair System, PD-L1 Expression, and Tumor Mutation Burden |
| title_short | Effects of a Novel Thiadiazole Derivative with High Anticancer Activity on Cancer Cell Immunogenic Markers: Mismatch Repair System, PD-L1 Expression, and Tumor Mutation Burden |
| title_sort | effects of a novel thiadiazole derivative with high anticancer activity on cancer cell immunogenic markers mismatch repair system pd l1 expression and tumor mutation burden |
| topic | thiadiazole derivative cancer immunogenic markers MMR impairment PD-L1 upregulation tumor mutation burden |
| url | https://www.mdpi.com/1999-4923/13/6/885 |
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