Your browser doesn't support javascript.
loading
Targeting neuropilin-1 abolishes anti-PD-1-upregulated regulatory T cells and synergizes with 4-1BB agonist for liver cancer treatment.
Wu, Qinchuan; Pan, Caixu; Zhou, Yuan; Wang, Shuai; Xie, Liting; Zhou, Wuhua; Ding, Limin; Chen, Tianchi; Qian, Junjie; Su, Rong; Gao, Xingxing; Mei, Zhibin; Qiao, Yiting; Yin, Shengyong; Wu, Yi; Wang, Jieyi; Zhou, Lin; Zheng, Shusen.
Afiliación
  • Wu Q; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • Pan C; NHFPC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China.
  • Zhou Y; Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment of Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, China.
  • Wang S; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • Xie L; NHFPC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China.
  • Zhou W; Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment of Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, China.
  • Ding L; Department of Thoracic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • Chen T; Division of Hepatobiliary and Pancreatic Surgery, Department of Liver Transplantation, Shulan Hospital, Zhejiang Shuren University School of Medicine, Hangzhou, China.
  • Qian J; Department of Ultrasound, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • Su R; Department of Hepatobiliary Pancreatic Surgery, Taihe Hospital, Hubei University of Medicine, Shiyan, China.
  • Gao X; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • Mei Z; NHFPC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China.
  • Qiao Y; Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment of Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, China.
  • Yin S; Department of vascular surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • Wu Y; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • Wang J; NHFPC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China.
  • Zhou L; Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment of Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, China.
  • Zheng S; NHFPC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China.
Hepatology ; 78(5): 1402-1417, 2023 11 01.
Article en En | MEDLINE | ID: mdl-36811396
BACKGROUND AIMS: Regulatory T cells (Tregs) are an obstacle to PD-1 blockade-mediated antitumor efficacy. However, the behaviors of Tregs response to anti-PD-1 in HCC and the characteristics of Tregs tissue adaptation from peripheral lymphoid tissues to the tumor are still unclear. APPROACH RESULTS: Here, we determine that PD-1 monotherapy potentially augments the accumulation of tumor CD4 + Tregs. Mechanistically, anti-PD-1 mediates Tregs proliferation in lymphoid tissues rather than in the tumor. Increased peripheral Tregs burden replenishes intratumoral Tregs, raising the ratio of intratumoral CD4 + Tregs to CD8 + T cells. Subsequently, single-cell transcriptomics revealed that neuropilin-1 (Nrp-1) supports Tregs migration behavior, and the genes of Crem and Tnfrsf9 regulate the behaviors of the terminal suppressive Tregs. Nrp-1 + 4-1BB - Tregs stepwise develop to the Nrp-1 - 4-1BB + Tregs from lymphoid tissues into the tumor. Moreover, Treg-restricted Nrp1 depletion abolishes anti-PD-1-upregulated intratumoral Tregs burden and synergizes with the 4-1BB agonist to enhance the antitumor response. Finally, a combination of the Nrp-1 inhibitor and the 4-1BB agonist in humanized HCC models showed a favorable and safe outcome and evoked the antitumor effect of the PD-1 blockade. CONCLUSION: Our findings elucidate the potential mechanism of anti-PD-1-mediated intratumoral Tregs accumulation in HCC and uncover the tissue adaptation characteristics of Tregs and identify the therapeutic potential of targeting Nrp-1 and 4-1BB for reprogramming the HCC microenvironment.
Asunto(s)
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma Hepatocelular / Microambiente Tumoral / Neoplasias Hepáticas Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Hepatology Año: 2023 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma Hepatocelular / Microambiente Tumoral / Neoplasias Hepáticas Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Hepatology Año: 2023 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos