Apurinic/apyrimidinic endonuclease 1 (APE1), which has the dual functions of both DNA repair and redox activity, has been reported to be highly expressed in non-small cell lung cancer (NSCLC), and this appears to be a characteristic related to chemotherapy resistance. In this study, we identified serum APE1 autoantibodies (APE1-AAbs) in NSCLC patients and healthy controls by immunoblotting and investigated the expression of APE1-AAbs by indirect ELISA from the serum of 292 NSCLC patients and 300 healthy controls. In addition, serum APE1-AAbs level alterations of 91 patients were monitored before and after chemotherapy. Our results showed that serum APE1-AAbs can be detected in both NSCLC patients and healthy controls. Serum APE1-AAbs were significantly higher than those of healthy controls and closely related to APE1 antigen levels both in tumor tissues and the peripheral blood. Moreover, the change in levels of serum APE1-AAbs in NSCLC is closely associated with the response to chemotherapy. These results suggest that APE1-AAbs is a potential tumor marker and predictor of therapeutic efficacy in NSCLC.

Base excision repair (BER) handles many forms of endogenous DNA damage, and apurinic/apyrimidinic endonuclease 1 (APE1) is central to this process. Deletion of both alleles of APE1 (a.k.a. Apex1) in mice leads to embryonic lethality, and deficiency in cells can promote cell death. Unlike most other BER proteins, APE1 expression is inversely correlated with cellular senescence in primary human fibroblasts. Depletion of APE1 via shRNA induced senescence in normal human BJ fibroblasts, a phenotype that was not seen in counterpart cells expressing telomerase. APE1 knock-down in primary fibroblasts resulted in global DNA damage accumulation, and the induction of p16INK4a and p21WAF1 stress response pathways; the DNA damage response, as assessed by γ-H2AX, was particularly pronounced at telomeres. Conditional knock-out of Apex1 in mice at post-natal day 7/12 resulted in impaired growth, reduced organ size, and increased cellular senescence. The effect of Apex1 deletion at post-natal week 6 was less obvious, other than cellular senescence, until ∼8-months of age, when premature aging characteristics, such as hair loss and impaired wound healing, were seen. Low APE1 expression in patient cancer tissue also correlated with increased senescence. Our results point to a key role for APE1 in regulating cellular senescence and aging features, with telomere status apparently affecting the outcome.

BackgroundEpithelial‐to‐mesenchymal transition (EMT) plays a pivotal role in resistance to EGFR tyrosine kinase inhibitors (TKIs) in non‐small‐cell lung cancer (NSCLC). Our previous study revealed that in osteosarcoma, human apurinic/apyrimidinic endonuclease 1 (APE1) regulates transforming growth factor‐β (TGF‐β), an important player in EMT. We therefore hypothesized a link between APE1 and EGFR‐TKI responsiveness in NSCLC.MethodsThe protein levels of APE1 were analyzed in tumors of NSCLC patients receiving EGFR‐TKI treatment. The correlation between APE1 expression and progression‐free survival (PFS), overall survival (OS), or response rate were analyzed. The impact of APE1 on the response to EGFR‐TKIs was measured by exogenous manipulation of APE1 in EGFR‐TKI‐sensitive and EGFR‐TKI‐resistant cells.ResultsWe indicate that low expression of APE1 in tumors is associated with a significantly longer PFS (20.8 months vs 8.4 months, P = 0.008) and a preferential OS (39.0 months vs 17.0 months, P = 0.001), with no difference in initial response rate to EGFR‐TKIs. We observed that APE1 protein level was significantly increased in EGFR‐TKI‐resistant cells and was associated with downregulated E‐cadherin and upregulated vimentin. The EMT phenotype, as well as the levels of TGF‐β, was suppressed in APE1 knockdown HCC827/IR and PC‐9/ER cells, while the EMT phenotype was promoted in APE1‐overexpressed HCC827 and PC‐9 cells. Furthermore, a specific APE1 redox inhibitor (ie, E3330) effectively reversed the EMT phenotype and further sensitized the cells to EGFR‐TKIs.ConclusionThis study revealed a significant role of APE1 in EGFR‐TKI resistance via novel regulatory effects on the EMT phenotype in NSCLC.

BackgroundSeveral immune checkpoint inhibitors (ICIs), represented by programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) antibodies, have been approved for treatment of various malignant tumors (including advanced esophageal cancer) worldwide, and previous studies confirmed that they can significantly improve overall survival.1 However, there has been limited research on the use of ICIs as neoadjuvant therapy for patients with esophageal cancer. Toripalimab is a humanized IgG4 monoclonal antibody that targets PD-1. The objective of this study is to evaluate the efficacy and safety of toripalimab plus chemotherapy as a neoadjuvant therapy regimen for treatment of patients with locally advanced esophageal squamous cell carcinoma (ESCC).MethodsThis single-arm, single-center study enrolled patients with ESCC at clinical stage T2-T4/N0-N2/M0, who were eligible for radical resection and regional lymph node dissection. The patients received 2–3 cycles of toripalimab (240 mg d1, Q3W) in combination with nab-paclitaxel (260 mg/m2 d1, Q3W) and carboplatin (AUC=5 d1, Q3W) before surgery. Preoperative evaluation was performed within 4 weeks after the last administration of chemotherapy. The primary endpoints were pathologic complete response (PCR) and major pathologic response (MPR), and the secondary endpoints were safety and feasibility of the neoadjuvant immunotherapy.ResultsSeventeen patients diagnosed with ESCC at a pre-treatment clinical stage of T2-T4/N0-N2/M0 were included. After neoadjuvant therapy, 15 of 17 patients (88.2%) experienced downstaging and met the surgical criteria. Twelve patients (80.0%) underwent surgery without delay and 3 patients (20.0%) refused surgery. The tumors were completely removed in all 12 patients (R0 resection rate: 100%). Seven patients (58.3%) achieved MPR and 2 (16.7%) achieved PCR. The median post-surgical follow-up time was 4.5 months, and there were no recurrences. Treatment-related adverse events (TRAEs) of the neoadjuvant therapy were tolerable. Grade 3 or higher TRAEs occurred in 2 patients (11.8%), but these did not delay surgery.ConclusionsToripalimab in combination with chemotherapy as neoadjuvant therapy showed promising anti-tumor activity with acceptable tolerance for locally advanced ESCC, as demonstrated by reducing the tumor burden, improving the R0 resection rate, reducing the postoperative recurrence rate, and no delays in surgery.AcknowledgementsN/AEthics ApprovalThis study was approved by the Ethics Board of the Army Medical center of the PLA, approval number 142(2018).ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.ReferenceWu X, Gu Z, Chen Y, et al. Application of PD-1 blockade in cancer immunotherapy. Comput Struct Biotechnol J 2019;17:661–674.

No abstract