인문학
사회과학
자연과학
공학
의약학
농수해양학
예술체육학
복합학
DBpia AI
AI 에이전트
AI 아이디어
AI 리더
AI 뷰어
Citeasy
크롬 서지관리 다운로드
지원사업
학술연구/단체지원/교육 등 연구자 활동을 지속하도록 DBpia가 지원하고 있어요.
커뮤니티
연구자들이 자신의 연구와 전문성을 널리 알리고, 새로운 협력의 기회를 만들 수 있는 네트워킹 공간이에요.
초록·키워드
High levels of replication stress make cancer cells vulnerable to therapies targeting DNA damage response (DDR) proteins, such as ataxia telangiectasia and Rad3-related (ATR) protein kinase. ATR is a key mediator of the replication stress response and plays a vital role in maintaining genomic stability. This study investigates the immunomodulatory potential of the ATR inhibitor (ATRi) tuvusertib to improve the targeting of prostate cancer (PCa) by immunotherapy. Tuvusertib pretreatment sensitized human PCa cells (DU145 and 22Rv1) to PBMC-derived natural killer (NK)-mediated lysis. Flow cytometric analysis identified upregulation of death receptor tumor-necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2), NKG2D ligand ULBP-1, and programmed death-ligand 1 (PD-L1) as a potential immunomodulatory effect of tuvusertib. Enhanced avelumab-mediated antibody-dependent cell-mediated cytotoxicity and lysis by PD-L1 targeting high-affinity NK (PD-L1 t-haNK) cells were observed in tuvusertib-treated DU145. Tuvusertib sensitized cells to lysis by recombinant human TRAIL, and TRAIL signaling blockade reduced NK-mediated lysis of tuvusertib-exposed cells. RNA analysis revealed elevated p21 and reduced Bcl-xL transcript levels in tuvusertib-treated DU145, suggesting an accumulation of DNA damage and suppression of anti-apoptotic signaling, respectively. Pretreatment of NK cells with the interleukin-15 (IL-15) receptor superagonist N-803 (nogapendekin alfa inbakicept) further enhaced the lysis of tuvusertib-exposed cells. In vivo in the DU145 PCa xenograft model, tuvusertib and N-803 combination therapy demonstrated marked and significant antitumor efficacy relative to either monotherapy, eliciting superior tumor growth control and prolonging survival. Our findings support further investigation into the use of ATRi with immune checkpoint blockade and/or immune-stimulating agents in prostate cancer.
인공지능 문자 인식 모델을 통해 추출된 텍스트로, 일부 오타나 오류가 포함될 수 있으나 지속적으로 개선 중입니다.
오류를 발견하셨다면 해당 부분을 드래그한 후 ' 를 통해 신고해주세요.
오류를 발견하셨다면 해당 부분을 드래그한 후 ' 를 통해 신고해주세요.
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