The Role of CD40 Activation in Tumor Immunology and Immunotherapy

To discern the role of CD40 in tumor immunity using laboratory model systems and identify the optimal strategy to deploy CD40 activation for cancer immunotherapeutics.


  • Perform CD40 gain-of-function and loss-of-function studies in vivo in tumor bearing mice (pancreas cancer and melanoma)
  • Understand TME in genetic murine mouse models, including cell composition and inflammatory  networks
  • Evaluate murine agonist CD40 mAb and the biomarkers of response and resistance
  • Evaluate preclinical models of CD40 combinations including chemotherapy, checkpoint blockade, and radiation


  • We have reported the mechanisms of immune activation of CD40 and chemotherapy in murine pancreatic cancer (including DC activation, Treg depletion, and clonal T cell expansion) and demonstrated that CD40 activation obviates the need for immune sensors such as IFNAR and STING.
  • We have dissected the dynamics and mechanism of CSF1R-dependent hepatotoxicity when CD40 is given prior to chemotherapy in murine models
  • We have identified the role of CXCR2 ligands in human and mouse pancreatic cancer in the regulation of neutrophilic tumor infiltration and its suppression of T cell immunity; we demonstrated novel signal pathways and identify CXCR2 has a novel immunotherapeutic target
  • We have established a 60 tumor clone panel to model tumor immune heterogeneity, demonstrating immunotherapy correlates with T cell content and that T cell content is driven by tumor intrinsic sculpting of the myeloid TME
  • We have established using random forest machine learning tools that CD40 is a non-redundant and necessary activation pathway that sensitizes pancreatic cancer to radiation therapy and checkpoint blockade

Byrne and Vonderheide Cell Reports 2016

Byrne et al, J. Immunol, 2016

Chao et al, Can Immunol Res 2016

Project Participants: Robert Vonderheide, Mark Diamond, Jeffrey Lin, Tim Chao, Andrew Rech, Katelyn T. Byrne (Parker Fellow) (PICI@Penn Directory)