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. 2023 Feb 7;12(4):530. doi: 10.3390/cells12040530

Figure 2.

Figure 2

Effect of irinotecan and etoposide on the DNA damage (DDR) and immune response. Cancer cell (A) Irinotecan inhibits DNA topoisomerase I which leads to the formation of single-strand breaks (SSBs) and double-strand breaks (DSBs). Single-stranded DNA (ssDNA) in the replication fork that arises due to helicase activity is coated with replication protein A (RPA) protein and a mediator of DNA damage checkpoint protein 1 (MDC-1). MDC-1 serves as a platform protein for topoisomerase 2-binding protein 1 (TOPBP1), ATR-interacting protein (ATRIP), and serine/threonine-protein kinase (ATR). In contrast, DSBs that arise through the conversion of SSBs and activity of topoisomerase II inhibitors (here etoposide) are detected by the MRN complex composed of double-strand break repair protein MRE11 (MRE11), nibrin (NBS1), and DNA repair protein (RAD50). The MRN complex is involved in the recruitment and activation of ATM kinase. Activated ATR and ATM phosphorylate have multiple targets including checkpoint kinases (CHK1/2). The phosphorylation of H2AX and accumulation of MDC-1 contribute to further recruitment of ATR/ATM kinases and amplification of damage signaling. CHK1 activation leads to the phosphorylation of signal transducers and activator of transcription (STAT) proteins that control (up-regulate) the expression of interferon regulatory factor (IRF1) and the major histocompatibility complex class I molecule (MHC-I). IRF-1 works as a transcription factor for programmed death ligand-1 (PD-L1) protein. Tumor immune microenvironment (B) Topoisomerase inhibitors stimulate the anti-tumor immune response through the increased proliferation and infiltration of CD8+ cells and the production of immunostimulatory interferon gamma (INFγ). INFγ binds to and activates the interferon-gamma receptor (INFGR) that contributes to the activation of tyrosine-protein kinase JAK (JAK)/STAT signaling to confer the increased PD-L1 expression. Moreover, it also reduces the regulatory FOXP3+ T-cells and myeloid-derived suppressor cells (MDSC) that normally attenuate the anti-tumor immune response. Cells defective in double-strand break repair components (C): Inactivation of the breast cancer type 2 susceptibility protein (BRCA2) of homologous recombination (HR) pathway and X-ray repair cross-complementing protein 5/6 (KU70/80) of the non-homologous end joining (NHEJ) pathway contributes to the activation of CHK1/STAT/IRF/PD-L1 signaling. Created with BioRender.com accessed on 1 February 2023.