Using a Kras-driven PDAC mouse model, Alam et al. showed that anti-TNFR1 Ab therapy or Tnfr1 KO increased TME numbers of DCs, IFNγ/TNFα-producing TILs, and T cell-dependent DC activation, and inhibited tumor growth. Anti-PD-1 treatment had a minor impact on s.c. PDAC growth in WT mice, but increased anti-TNFR1-induced IFNγ/TNFα production by TILs. anti-TNFR1 + anti-PD-1 treatment increased numbers/activation of DCs infiltrating Kras-driven spontaneous tumors. Anti-TNFR1 alone had a greater impact than Flt3L + anti-CD40 agonistic Ab, potentially due to inhibition of TNF/TNFR1-mediated DC apoptosis, shown in vitro. DC numbers inversely correlated with TNFR1 expression in human PDAC.
Contributed by Paula Hochman
ABSTRACT: Pancreatic adenocarcinoma (PDAC) is one the most intractable cancers, in part due to its highly inflammatory microenvironment and paucity of infiltrating dendritic cells (DCs). Here, we find that genetic ablation or antibody blockade of tumor necrosis factor receptor 1 (TNFR1) enhanced intratumor T cell activation and slowed PDAC growth. While anti-PD-1 checkpoint inhibition alone had little effect, it further enhanced intratumor T cell activation in combination with anti-TNFR1. The major cellular alteration in the tumor microenvironment in the absence of TNFR1 signaling was a large increase in DC number and immunostimulatory phenotype. This may reflect a direct effect on DCs, because TNF induced TNFR1-dependent apoptosis of bone-marrow-derived DCs. The therapeutic response to anti-TNFR1 alone was superior to the combination of DC-activating agonistic anti-CD40 and Flt3 ligand (Flt3L). These observations suggest that targeting TNFR1, perhaps in concert with other strategies that promote DC generation and mobilization, may have therapeutic benefits.
Author Info: (1) Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: alamms@mai
Author Info: (1) Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: alamms@mail.nih.gov. (2) Institute of Pathology, University Medical Center Mainz, JGU-Mainz, 55131 Mainz, Germany; TRON, Translational Oncology at the University Medical Center, JGU-Mainz, 55131 Mainz, Germany; Research Center for Immunotherapy, University Medical Center Mainz, JGU-Mainz, 55131 Mainz, Germany. (3) Institute of Pathology, University Medical Center Mainz, JGU-Mainz, 55131 Mainz, Germany. (4) Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (5) Department of Integrative Immunobiology, Duke University, Durham, NC 27708, USA. (6) Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21707, USA. (7) Collaborative Bioinformatics Resource (CCBR), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. (8) Collaborative Bioinformatics Resource (CCBR), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (9) Collaborative Bioinformatics Resource (CCBR), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. (10) Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21707, USA. (11) Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: jda@pop.nci.nih.gov.
