Laurence P Diggs1, Benjamin Ruf2, Chi Ma2, Bernd Heinrich2, Linda Cui2, Qianfei Zhang2, John C McVey2, Simon Wabitsch2, Sophia Heinrich3, Umberto Rosato2, Walter Lai2, Varun Subramanyam2, Thomas Longerich4, Sven H Loosen5, Tom Luedde5, Ulf Peter Neumann6, Sabina Desar7, David Kleiner7, Gregory Gores8, Xin Wei Wang9, Tim F Greten10. 1. Thoracic & GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. 2. Thoracic & GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. 3. Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. 4. Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. 5. Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Germany. 6. Department of Visceral and Transplantation Surgery, University Hospital RWTH Aachen Aachen, Germany. 7. Laboratory of Pathology, National Institutes of Health, Bethesda, Maryland, USA. 8. Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA. 9. Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; NCI CCR Liver Cancer Program, National Institutes of Health, Bethesda, Maryland 20892, USA. 10. Thoracic & GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; NCI CCR Liver Cancer Program, National Institutes of Health, Bethesda, Maryland 20892, USA. Electronic address: tim.greten@nih.gov.
Abstract
BACKGROUND & AIMS: While cholangiocarcinomas (CCAs) commonly express programmed cell death 1 (PD-1) and its ligand (PD-L1), they respond poorly to immune checkpoint inhibitors (ICIs). We aimed to determine whether stimulating antigen-presenting cells, including macrophages and dendritic cells, using a CD40 agonist could improve this response. METHODS: We compared treatment responses in subcutaneous, orthotopic, and 2 plasmid-based murine intrahepatic CCA (iCCA) models. Mice were treated for 4 weeks with weekly IgG control, a CD40 agonistic antibody, anti-PD-1, or the combination of both (anti-CD40/PD-1). Flow cytometric (FACS) analysis of lymphocytes and myeloid cell populations (including activation status) was performed. We used dendritic cell knockout mice, and macrophage, CD4+ and CD8+ T cell depletion models to identify effector cells. Anti-CD40/PD-1 was combined with chemotherapy (gemcitabine/cisplatin) to test for improved therapeutic efficacy. RESULTS: In all 4 models, anti-PD-1 alone was minimally efficacious. Mice exhibited a moderate response to CD40 agonist monotherapy. Combination anti-CD40/PD-1 therapy led to a significantly greater reduction in tumor burden. FACS demonstrated increased number and activation of CD4+ and CD8+ T cells, natural killer cells, and myeloid cells in tumor and non-tumor liver tissue of tumor-bearing mice treated with anti-CD40/PD-1. Depletion of macrophages, dendritic cells, CD4+ T cells, or CD8+ T cells abrogated treatment efficacy. Combining anti-CD40/PD-1 with gemcitabine/cisplatin resulted in a significant survival benefit compared to gemcitabine/cisplatin alone. CONCLUSION: CD40-mediated activation of macrophages and dendritic cells in iCCA significantly enhances response to anti-PD-1 therapy. This regimen may enhance the efficacy of first-line chemotherapy. LAY SUMMARY: Checkpoint inhibition, a common form of immune therapy, is generally ineffective for the treatment of cholangiocarcinoma. These tumors suppress the infiltration and function of surrounding immune cells. Stimulating immune cells such as macrophages and dendritic cells via the CD40 receptor activates downstream immune cells and enhances the response to checkpoint inhibitors. Published by Elsevier B.V.
BACKGROUND & AIMS: While cholangiocarcinomas (CCAs) commonly express programmed cell death 1 (PD-1) and its ligand (PD-L1), they respond poorly to immune checkpoint inhibitors (ICIs). We aimed to determine whether stimulating antigen-presenting cells, including macrophages and dendritic cells, using a CD40 agonist could improve this response. METHODS: We compared treatment responses in subcutaneous, orthotopic, and 2 plasmid-based murine intrahepatic CCA (iCCA) models. Mice were treated for 4 weeks with weekly IgG control, a CD40 agonistic antibody, anti-PD-1, or the combination of both (anti-CD40/PD-1). Flow cytometric (FACS) analysis of lymphocytes and myeloid cell populations (including activation status) was performed. We used dendritic cell knockout mice, and macrophage, CD4+ and CD8+ T cell depletion models to identify effector cells. Anti-CD40/PD-1 was combined with chemotherapy (gemcitabine/cisplatin) to test for improved therapeutic efficacy. RESULTS: In all 4 models, anti-PD-1 alone was minimally efficacious. Mice exhibited a moderate response to CD40 agonist monotherapy. Combination anti-CD40/PD-1 therapy led to a significantly greater reduction in tumor burden. FACS demonstrated increased number and activation of CD4+ and CD8+ T cells, natural killer cells, and myeloid cells in tumor and non-tumor liver tissue of tumor-bearing mice treated with anti-CD40/PD-1. Depletion of macrophages, dendritic cells, CD4+ T cells, or CD8+ T cells abrogated treatment efficacy. Combining anti-CD40/PD-1 with gemcitabine/cisplatin resulted in a significant survival benefit compared to gemcitabine/cisplatin alone. CONCLUSION: CD40-mediated activation of macrophages and dendritic cells in iCCA significantly enhances response to anti-PD-1 therapy. This regimen may enhance the efficacy of first-line chemotherapy. LAY SUMMARY: Checkpoint inhibition, a common form of immune therapy, is generally ineffective for the treatment of cholangiocarcinoma. These tumors suppress the infiltration and function of surrounding immune cells. Stimulating immune cells such as macrophages and dendritic cells via the CD40 receptor activates downstream immune cells and enhances the response to checkpoint inhibitors. Published by Elsevier B.V.
Entities:
Keywords:
Antigen-presenting cell; CD40 agonist; Cholangiocarcinoma; Dendritic cell; Immune checkpoint; Immunotherapy; Liver cancer; Macrophage; NK cell; T cell; Tumor-infiltrating lymphocyte
Authors: Chi Ma; Qiong Fu; Laurence P Diggs; John C McVey; Justin McCallen; Simon Wabitsch; Benjamin Ruf; Zachary Brown; Bernd Heinrich; Qianfei Zhang; Umberto Rosato; Sophie Wang; Linda Cui; Jay A Berzofsky; David E Kleiner; Dale B Bosco; Long-Jun Wu; Chunwei Walter Lai; Yaron Rotman; Changqing Xie; Firouzeh Korangy; Tim F Greten Journal: Cancer Cell Date: 2022-09-01 Impact factor: 38.585
Authors: María Gutiérrez-Larrañaga; Elena González-López; Adriel Roa-Bautista; Pedro M Rodrigues; Álvaro Díaz-González; Jesus M Banales; Marcos López-Hoyos; Alvaro Santos-Laso; Javier Crespo Journal: Liver Cancer Date: 2021-09-21 Impact factor: 11.740