Targeting neuropilin-1 abolishes anti-PD-1-upregulated regulatory T cells and synergizes with 4-1BB agonist for liver cancer treatment

Author:

Wu Qinchuan123ORCID,Pan Caixu123,Zhou Yuan4,Wang Shuai5,Xie Liting6,Zhou Wuhua7,Ding Limin123,Chen Tianchi8,Qian Junjie123,Su Rong23,Gao Xingxing123,Mei Zhibin123,Qiao Yiting123,Yin Shengyong23,Wu Yi9,Wang Jieyi9,Zhou Lin123,Zheng Shusen1235ORCID

Affiliation:

1. Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China

2. NHFPC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China

3. 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

4. Department of Thoracic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China

5. Division of Hepatobiliary and Pancreatic Surgery, Department of Liver Transplantation, Shulan Hospital, Zhejiang Shuren University School of Medicine, Hangzhou, China

6. Department of Ultrasound, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China

7. Department of Hepatobiliary Pancreatic Surgery, Taihe Hospital, Hubei University of Medicine, Shiyan, China

8. Department of vascular surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China

9. Lyvgen Biopharma, Shanghai, China

Abstract

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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Hepatology

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