| Autor: |
Morita S; Massachusetts General Hospital, Boston, MA, United States., Lei PJ; Massachusetts General Hospital, Boston, MA, United States., Shigeta K; Keio University, Tokyo, Japan., Ando T; Massachusetts General Hospital, Boston, MA, United States., Kobayashi T; Tokyo Women's Medical University, Shinjuku, Tokyo, Japan., Kikuchi H; Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States., Matsui A; Kanazawa University, Kanazawa, Japan., Huang P; Massachusetts General Hospital, Harvard Medical School, Boston, United States., Pittet MJ; University of Geneva, Lausanne, Switzerland., Duda DG; Massachusetts General Hospital, Boston, MA, United States. |
| Abstrakt: |
Immune checkpoint inhibitors (ICIs) 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 (DCs) in liver malignancies. Here, we tested combination blockade of programmed death receptor 1 (PD1) 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. Combination anti-CXCR4 and anti-PD1therapy 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 (cDC1s) 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/PD1 therapy was compromised entirely in Batf3-KO mice deficient in cDC1s. Thus, combined CXCR4/PD1 blockade can reprogram intra-tumoral cDC1s and holds the potential to potentiate antitumor immune response against HCC. |
