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Autophagy deficiency promotes triple-negative breast cancer resistance to T cell-mediated cytotoxicity by blocking tenascin-C degradation.
- Source :
- Nature Communications; 7/30/2020, Vol. 11 Issue 1, p1-19, 19p
- Publication Year :
- 2020
-
Abstract
- Most triple-negative breast cancer (TNBC) patients fail to respond to T cell-mediated immunotherapies. Unfortunately, the molecular determinants are still poorly understood. Breast cancer is the disease genetically linked to a deficiency in autophagy. Here, we show that autophagy defects in TNBC cells inhibit T cell-mediated tumour killing in vitro and in vivo. Mechanistically, we identify Tenascin-C as a candidate for autophagy deficiency-mediated immunosuppression, in which Tenascin-C is Lys63-ubiquitinated by Skp2, particularly at Lys942 and Lys1882, thus promoting its recognition by p62 and leading to its selective autophagic degradation. High Tenascin-C expression is associated with poor prognosis and inversely correlated with LC3B expression and CD8<superscript>+</superscript> T cells in TNBC patients. More importantly, inhibition of Tenascin-C in autophagy-impaired TNBC cells sensitizes T cell-mediated tumour killing and improves antitumour effects of single anti-PD1/PDL1 therapy. Our results provide a potential strategy for targeting TNBC with the combination of Tenascin-C blockade and immune checkpoint inhibitors. T cell mediated therapies have proven largely unsuccessful in triple-negative breast cancer (TNBC). Here, the authors show that autophagy is reduced in TNBC, which results in an increase in Tenascin C and reduced activation of tumour infiltrating lymphocytes. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 11
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Nature Communications
- Publication Type :
- Academic Journal
- Accession number :
- 144855807
- Full Text :
- https://doi.org/10.1038/s41467-020-17395-y