Pharmacological disruption of the MTDH–SND1 complex enhances tumor antigen presentation and synergizes with anti-PD-1 therapy in metastatic breast cancer

Minhong Shen, Heath A. Smith, Yong Wei, Yi Zhou Jiang, Sheng Zhao, Nicole Wang, Michelle Rowicki, Yong Tang, Xiang Hang, Songyang Wu, Liling Wan, Zhi Ming Shao, Yibin Kang

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Despite increased overall survival rates, curative options for metastatic breast cancer remain limited. We have previously shown that metadherin (MTDH) is frequently overexpressed in poor prognosis breast cancer, where it promotes metastasis and therapy resistance through its interaction with staphylococcal nuclease domain-containing 1 (SND1). Through genetic and pharmacological targeting of the MTDH–SND1 interaction, we reveal a key role for this complex in suppressing antitumor T cell responses in breast cancer. The MTDH–SND1 complex reduces tumor antigen presentation and inhibits T cell infiltration and activation by binding to and destabilizing Tap1/2 messenger RNAs, which encode key components of the antigen-presentation machinery. Following small-molecule compound C26-A6 treatment to disrupt the MTDH–SND1 complex, we showed enhanced immune surveillance and sensitivity to anti-programmed cell death protein 1 therapy in preclinical models of metastatic breast cancer, in support of this combination therapy as a viable approach to increase immune-checkpoint blockade therapy responses in metastatic breast cancer.

Original languageEnglish (US)
Pages (from-to)60-74
Number of pages15
JournalNature Cancer
Volume3
Issue number1
DOIs
StatePublished - Jan 2022

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research
  • Medicine(all)

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