C4b-binding protein α-chain enhances antitumor immunity by facilitating the accumulation of tumor-infiltrating lymphocytes in the tumor microenvironment in pancreatic cancer View Full Text


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Article Info

DATE

2021-06-24

AUTHORS

Kosuke Sasaki, Shigetsugu Takano, Satoshi Tomizawa, Yoji Miyahara, Katsunori Furukawa, Tsukasa Takayashiki, Satoshi Kuboki, Mamoru Takada, Masayuki Ohtsuka

ABSTRACT

BackgroundRecent studies indicate that complement plays pivotal roles in promoting or suppressing cancer progression. We have previously identified C4b-binding protein α-chain (C4BPA) as a serum biomarker for the early detection of pancreatic ductal adenocarcinoma (PDAC). However, its mechanism of action remains unclear. Here, we elucidated the functional roles of C4BPA in PDAC cells and the tumor microenvironment.MethodsWe assessed stromal C4BPA, the C4BPA binding partner CD40, and the number of CD8+ tumor-infiltrating lymphocytes in resected human PDAC tissues via immunohistochemical staining. The biological functions of C4BPA were investigated in peripheral blood mononuclear cells (PBMCs) and human PDAC cell lines. Mouse C4BPA (mC4BPA) peptide, which is composed of 30 amino acids from the C-terminus and binds to CD40, was designed for further in vitro and in vivo experiments. In a preclinical experiment, we assessed the efficacy of gemcitabine plus nab-paclitaxel (GnP), dual immune checkpoint blockades (ICBs), and mC4BPA peptide in a mouse orthotopic transplantation model.ResultsImmunohistochemical analysis revealed that high stromal C4BPA and CD40 was associated with favorable PDAC prognosis (P=0.0005). Stromal C4BPA strongly correlated with the number of CD8+ tumor-infiltrating lymphocytes (P=0.001). In in vitro experiments, flow cytometry revealed that recombinant human C4BPA (rhC4BPA) stimulation increased CD4+ and CD8+ T cell numbers in PBMCs. rhC4BPA also promoted the proliferation of CD40-expressing PDAC cells. By contrast, combined treatment with gemcitabine and rhC4BPA increased PDAC cell apoptosis rate. mC4BPA peptide increased the number of murine T lymphocytes in vitro and the number of CD8+ tumor-infiltrating lymphocytes surrounding PDAC tumors in vivo. In a preclinical study, GnP/ICBs/mC4BPA peptide treatment, but not GnP treatment, led to the accumulation of a greater number of CD8+ T cells in the periphery of PDAC tumors and to greater tumor regression than did control treatment.ConclusionsThese findings demonstrate that the combination of GnP therapy with C4BPA inhibits PDAC progression by promoting antitumor T cell accumulation in the tumor microenvironment. More... »

PAGES

212

References to SciGraph publications

  • 2016-09-22. Identification of a novel serum biomarker for pancreatic cancer, C4b-binding protein α-chain (C4BPA) by quantitative proteomic analysis using tandem mass tags in BRITISH JOURNAL OF CANCER
  • 2009-11-11. Activation of human B cells by the agonist CD40 antibody CP-870,893 and augmentation with simultaneous toll-like receptor 9 stimulation in JOURNAL OF TRANSLATIONAL MEDICINE
  • 1998-06. T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions in NATURE
  • 2019-04-02. Fetal lung C4BPA induces p100 processing in human placenta in SCIENTIFIC REPORTS
  • 1999-07. Conversion of tumor-specific CD4+ T-cell tolerance to T-cell priming through in vivo ligation of CD40 in NATURE MEDICINE
  • 2008-07-27. Effective induction of high-titer antibodies by viral vector vaccines in NATURE MEDICINE
  • 1999-05-01. CD40 antibody evokes a cytotoxic T-cell response that eradicates lymphoma and bypasses T-cell help in NATURE MEDICINE
  • 1995. Functional CD40 Antigen on B Cells, Dendritic Cells and Fibroblasts in DENDRITIC CELLS IN FUNDAMENTAL AND CLINICAL IMMUNOLOGY
  • 2017-03-09. Beyond TNF: TNF superfamily cytokines as targets for the treatment of rheumatic diseases in NATURE REVIEWS RHEUMATOLOGY
  • 2019-05-21. Tumour microenvironment of pancreatic cancer: immune landscape is dictated by molecular and histopathological features in BRITISH JOURNAL OF CANCER
  • 1999-07-01. CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy in NATURE MEDICINE
  • 2021-06-01. Complement factor B regulates cellular senescence and is associated with poor prognosis in pancreatic cancer in CELLULAR ONCOLOGY
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    http://scigraph.springernature.com/pub.10.1186/s13046-021-02019-0

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    http://dx.doi.org/10.1186/s13046-021-02019-0

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1139128235

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/34167573


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