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

TitlePharmacological disruption of the MTDH-SND1 complex enhances tumor antigen presentation and synergizes with anti-PD-1 therapy in metastatic breast cancer.
Publication TypeJournal Article
Year of Publication2022
AuthorsShen, M, Smith, HA, Wei, Y, Jiang, Y-Z, Zhao, S, Wang, N, Rowicki, M, Tang, Y, Hang, X, Wu, S, Wan, L, Shao, Z-M, Kang, Y
JournalNat Cancer
Volume3
Issue1
Pagination60-74
Date Published2022 01
ISSN2662-1347
KeywordsAntigen Presentation, Breast Neoplasms, Endonucleases, Female, Humans, Membrane Proteins, Micrococcal Nuclease, Nuclear Proteins, RNA-Binding Proteins, Transcription Factors
Abstract

<p>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.</p>

DOI10.1038/s43018-021-00280-y
Alternate JournalNat Cancer
PubMed ID35121988
PubMed Central IDPMC8818088
Grant ListP30 CA072720 / CA / NCI NIH HHS / United States
R01 CA134519 / CA / NCI NIH HHS / United States