B7-H3 drives immunosuppression and Co-targeting with CD47 is a new therapeutic strategy in β-catenin activated melanomas

Pigment Cell Melanoma Res. 2023 Sep;36(5):407-415. doi: 10.1111/pcmr.13091. Epub 2023 Apr 21.


In melanoma, immune cell infiltration into the tumor is associated with better patient outcomes and response to immunotherapy. T-cell non-inflamed tumors (cold tumors) are associated with tumor cell-intrinsic Wnt/β-catenin activation, and are typically resistant to anti-PD-1 alone or in combination with anti-CTLA-4 therapy. Reversal of the 'cold tumor' phenotype and identifying new effective immunotherapies are challenges. We sought to investigate the role of a newer immunotherapy agent, B7-H3, in this setting. RNA sequencing was used to identify co-targeting strategies upon B7-H3 inhibition in a well-defined preclinical melanoma model driven by β-catenin. We found that immune checkpoint molecule B7-H3 confers a suppressive tumor microenvironment by modulating antiviral signals and innate immunity. B7-H3 inhibition led to an inflamed microenvironment, up-regulation of CD47/SIRPa signaling, and together with blockade of the macrophage checkpoint CD47 resulted in additive antitumor responses. We found that the antitumor effects of the B7-H3/CD47 antibody combination were dependent on cytokine signaling pathways (CCR5/CCL5 and IL4).

Keywords: B7-H3; Beta-catenin; CCR5; CD47; IL4; PD-1; immunotherapy; inflammation; metastatic melanoma; microenvironment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • B7-H1 Antigen
  • CD47 Antigen
  • Humans
  • Immunosuppression Therapy
  • Immunotherapy / methods
  • Melanoma* / therapy
  • Tumor Microenvironment
  • beta Catenin


  • B7-H1 Antigen
  • beta Catenin
  • CD47 Antigen
  • CD47 protein, human