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

Min Hsu, Tiphaine C. Martin, Nikki S. Vyas, Garrett Desman, Karen Mendelson, Basil Horst, Ramon E. Parsons, Julide Tok Celebi

Research output: Contribution to journalArticlepeer-review

Abstract

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).

Original languageEnglish
Pages (from-to)407-415
Number of pages9
JournalPigment Cell and Melanoma Research
Volume36
Issue number5
DOIs
StatePublished - Sep 2023

Keywords

  • B7-H3
  • Beta-catenin
  • CCR5
  • CD47
  • IL4
  • PD-1
  • immunotherapy
  • inflammation
  • metastatic melanoma
  • microenvironment

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