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CD40-mediated immune cell activation enhances response to anti-PD1 in murine intrahepatic cholangiocarcinoma.

Abstract：

BACKGROUND & AIMS:Cholangiocarcinoma (CCA) carries a very poor prognosis due to a typically late clinical presentation and a poor response to current therapeutics. While these tumors commonly express PD-1 and PD-L1, the response to immune checkpoint inhibitors (ICI) is poor. Stimulating antigen-presenting cells including macrophages and dendritic cells using a CD40 agonist can improve response to ICIs. METHODS:We treated C57BL/6 mice with a CD40 agonistic antibody, anti-PD-1, and the combination of anti-CD40/PD-1. We compared treatment responses in subcutaneous, orthotopic, and two plasmid based murine intrahepatic cholangiocarcinoma (iCCA) models. Mice were treated for four weeks with weekly IgG control, CD40 agonist, anti-PD-1, or anti-CD40/PD-1. Tumor burden was assessed. Flow cytometric (FACS) analysis of lymphocytes and myeloid cells populations including activation status was performed. Using dendritic cell knockout mice, macrophage, CD4+ and CD8+ T cell depletion we identified effector cells. Anti-CD40/PD-1 was combined with chemotherapy (Gem/Cis) to test for improved therapeutic efficacy. RESULTS:In all four models, anti-PD-1 alone was minimally efficacious. Mice exhibited a moderate response to CD40 agonist monotherapy. Combination anti-CD40/PD-1 offered a significantly greater reduction in tumor burden. FACS demonstrated increased number and activation of CD4+ and CD8+ T cells, NK cells, and myeloid cells in tumor and non-tumor liver tissue of tumor-bearing mice treated with anti-CD40/PD-1. Macrophage, dendritic cells, CD4+ and CD8+ T cell depletion experiments all demonstrated abrogation of treatment efficacy. Combining anti-CD40/PD-1 with Gem/Cis resulted in a significant survival benefit compared to Gem/Cis alone. CONCLUSION:CD40-mediated activation of macrophages and dendritic cells in iCCA significantly enhances response to anti-PD-1 therapy. This regimen may enhance efficacy of first-line chemotherapy.

journal_name

J Hepatol

journal_title

Journal of hepatology

authors

Diggs LP,Ruf B,Ma C,Heinrich B,Cui L,Zhang Q,McVey JC,Wabitsch S,Heinrich S,Rosato U,Lai W,Subramanyam V,Longerich T,Loosen SH,Luedde T,Neumann UP,Desar S,Kleiner D,Gores G,Wang XW,Greten TF

doi

10.1016/j.jhep.2020.11.037

subject

Has Abstract

pub_date

2020-12-01 00:00:00

eissn

0168-8278

issn

1600-0641

pii

S0168-8278(20)33824-1

pub_type

杂志文章

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CD40-mediated immune cell activation enhances response to anti-PD1 in murine intrahepatic cholangiocarcinoma.