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Unstable B7-H4 cell surface expression and T-cell redirection as a means of cancer therapy

Akira Iizuka1, Ryota Kondou1, Chizu Nonomura1

  • 1Division of Immunotherapy, Shizuoka Cancer Center Research Institute, Shizuoka 411-8777, Japan.

Oncology Reports
|September 17, 2016
PubMed

Insights

Researchers identified B7-homolog 4 (B7-H4) as a potential cancer target. Despite its overexpression in many cancers, its instability hinders antibody-dependent cellular cytotoxicity (ADCC), suggesting novel therapeutic strategies are needed.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • B7/CD28 family antibodies modulate tumor immunity.
  • B7-homolog 4 (B7-H4) is an immune checkpoint protein that negatively regulates immune responses.
  • B7-H4 is overexpressed in various human cancers and present in tumor tissues and immune cells.

Purpose of the Study:

  • To investigate the role of B7-H4 in cancer immunity.
  • To evaluate B7-H4 as a potential therapeutic target for cancer treatment.

Main Methods:

  • Comprehensive whole exome sequencing and gene expression profiling (Project HOPE) on 1,058 cancer patient samples.
  • Production of monoclonal antibodies against B7-H4.
  • Analysis of B7-H4 dimerization and cell surface dynamics in breast cancer cells.
  • Indirect antibody-dependent cellular cytotoxicity (ADCC)-redirecting T-cell cytotoxicity assay.

Main Results:

  • Upregulation of B7-H4 expression was observed in a large cohort of cancer patients.
  • B7-H4 undergoes dimerization and rapid cell surface disappearance upon antibody cross-linking.
  • The instability of B7-H4 on the cell surface may explain the lack of in vivo ADCC efficacy.
  • An indirect T-cell cytotoxicity assay demonstrated the potential for targeting B7-H4.

Conclusions:

  • B7-H4 is a promising target for cancer therapy.
  • The dynamic nature of B7-H4 cell surface expression presents challenges for traditional ADCC-based therapies.
  • Novel strategies, such as indirect T-cell redirection, may be effective for targeting B7-H4 in cancer treatment.

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