Abstract
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-b]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.
Highlights
Our studies support that topoisomerase IIα is a potential target of the tested TATDADs, which act as topIIα inhibitors on the phosphorylation at Ser-1106 that is closely associated with the decatenation activity of the enzyme
The impact of the KA39 triazolo[3,4-b]thiadiazole derivative was investigated on three predictive biomarkers for cancer immunotherapy: programmed cell death ligand-1 (PD-L1), Microsatellite instability (MSI), and tumor mutation burden (TMB)
A notable increase in PD-L1 expression and MSI was demonstrated, presumably in the context of DNA damage introduced by KA39, while no changes in the TMB were induced
Summary
Three newly synthesized triazolo[3,4-b]thiadiazole derivatives (TATDADs) induced efficient cell growth inhibitory activity against three human colorectal cancer cell lines [5]. In vitro studies conducted on three human ovarian, two colorectal, and two prostate cancer cell lines have demonstrated significant antiproliferative activity induced by these compounds [6]. Targeting immune checkpoints, including PD-L1/PD-1, induce more prolonged therapeutic responses than conventional chemotherapy, indicating that immunotherapy is a valuable tool in cancer cure [7]. The present study intends to explore potential alterations in PD-L1, MSI, and TMB predictive biomarkers upon cell treatment with KA39 (Figure 1; Table 1), a TATDAD with high anticancer activity. Three human colorectal and two prostate cancer cell lines were selected, of which some were mismatch repair deficient (dMMR)/MSI-H, while others were mismatch repair proficient (pMMR)/microsatellite stable (MSS) (Table 2). Changes in PD-L1 expression were evaluated in tumor cells treated with KA39, as well as the TMB, in order to investigate whether KA39 triggers an increase in the overall number of somatic mutations
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
