• Home
  1. Home
  2. Combination CXCR4 and PD-1 Blockade Enhances Intratumoral Dendritic Cell Activation and Immune Responses Against Hepatocellular Carcinoma
Scientific article
OA Policy
English

Combination CXCR4 and PD-1 Blockade Enhances Intratumoral Dendritic Cell Activation and Immune Responses Against Hepatocellular Carcinoma

Contributors

Morita, Satoru; Lei, Pin-Ji; Shigeta, Kohei; Ando, Tomofumi; Kobayashi, Tatsuya; Kikuchi, Hiroto; Matsui, Aya; Huang, Peigen; Pittet, Mikaël; Duda, Dan G

Published in

Cancer immunology research, vol. 13, no. 2, p. 162-170

Publication date

2025-02-03

First online date

2024-11-08

Abstract

Immune checkpoint inhibitors have revolutionized the treatment of unresectable hepatocellular carcinoma (HCC), but their impressive efficacy is seen in just a fraction of patients. One key mechanism of immunotherapy resistance is the paucity of dendritic cells (DC) in liver malignancies. In this study, we tested combination blockade of PD-1 and CXCR4, a receptor for CXCL12, a pleiotropic factor that mediates immunosuppression in tumors. Using orthotopic grafted and autochthonous HCC models with underlying liver damage, we evaluated treatment feasibility and efficacy. In addition, we examined the effects of treatment using immunofluorescence, flow cytometric analysis of DCs in vivo and in vitro, and RNA sequencing. The combination anti-CXCR4 and anti-PD-1 therapy was safe and significantly inhibited tumor growth and prolonged survival in all murine preclinical models of HCC tested. The combination treatment successfully reprogrammed antigen-presenting cells, revealing the potential role of conventional type 1 DCs (cDC1) in the HCC microenvironment. Moreover, DC reprogramming enhanced anticancer immunity by facilitating CD8+ T-cell accumulation and activation in the HCC tissue. The effectiveness of anti-CXCR4/PD-1 therapy was compromised entirely in Batf3 knockout mice deficient in cDC1s. Thus, combined CXCR4/PD-1 blockade can reprogram intratumoral cDC1s and holds the potential to potentiate antitumor immune response against HCC.

Keywords

  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • Carcinoma, Hepatocellular / drug therapy
  • Carcinoma, Hepatocellular / immunology
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immunotherapy / methods
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / immunology
  • Liver Neoplasms / pathology
  • Mice
  • Mice, Inbred C57BL
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Receptors, CXCR4 / antagonists & inhibitors
  • Receptors, CXCR4 / immunology
  • Tumor Microenvironment / immunology

UNIGE affiliation entities

UNIGE research groups

Funding

  • Bristol Myers Squibb Foundation [SRA]
  • National Cancer Institute [R01CA260857]
  • U.S. Department of Defense [W81XWH-19-1-0284]
  • NCI NIH HHS [R01 CA247441]

Citation (ISO format)

MORITA, Satoru et al. Combination CXCR4 and PD-1 Blockade Enhances Intratumoral Dendritic Cell Activation and Immune Responses Against Hepatocellular Carcinoma. In: Cancer immunology research, 2025, vol. 13, n° 2, p. 162–170. doi: 10.1158/2326-6066.cir-24-0324

Main files (1)

Article (Published version)
CC BY-NC-ND-4.0

Identifiers

Additional URL for this publication

https://aacrjournals.org/cancerimmunolres/article/13/2/162/751247/Combination-CXCR4-and-PD-1-Blockade-Enhances

Journal ISSN

2326-6066
55views
31downloads

Technical informations

Creation

10/10/2025 13:00:27

First validation

08/12/2025 15:41:00

Update

08/12/2025 15:41:00

Status update

08/12/2025 15:41:00

Last indexation

08/12/2025 15:41:01
All rights reserved by Archive ouverte UNIGE and the University of Geneva
OpenAIRE Indexed & Validated