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

Authors :
Shen M
Smith HA
Wei Y
Jiang YZ
Zhao S
Wang N
Rowicki M
Tang Y
Hang X
Wu S
Wan L
Shao ZM
Kang Y
Source :
Nature cancer [Nat Cancer] 2022 Jan; Vol. 3 (1), pp. 60-74. Date of Electronic Publication: 2021 Nov 29.
Publication Year :
2022

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.<br /> (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Details

Language :
English
ISSN :
2662-1347
Volume :
3
Issue :
1
Database :
MEDLINE
Journal :
Nature cancer
Publication Type :
Academic Journal
Accession number :
35121988
Full Text :
https://doi.org/10.1038/s43018-021-00280-y