Autophagy Deficiency Promotes Triple-Negative Breast Cancer Resistance to T Cell-Mediated Cytotoxicity by Blocking Tenascin-C Degradation

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 promotes tumour immune response, and autophagy defects inhibit T cell-mediated killing in TNBC tumours. Mechanistically, we identify Tenascin-C as a strong candidate for autophagy deficiency-mediated immunosuppression, in which Tenascin-C is Lys63-ubiquitinated by Skp2, particularly at Lys924 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+ 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/PD-L1 therapy. Our results provide a potential strategy against TNBC with the combination of Tenascin-C blockade and immune checkpoint inhibitors.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Rong Deng  

LAB HEAD: Rong Deng

PROVIDER: PXD019946 | Pride | 2020-08-05

REPOSITORIES: Pride