Autophagy deficiency promotes triple-negative breast cancer resistance to T cell-mediated cytotoxicity by blocking tenascin-C degradation

• Published in: Nature communications Vol. 11; no. 1; pp. 3806 - 19
• Main Authors: Li, Zhi-Ling, Zhang, Hai-Liang, Huang, Yun, Huang, Jun-Hao, Sun, Peng, Zhou, Ning-Ning, Chen, Yu-Hong, Mai, Jia, Wang, Yan, Yu, Yan, Zhou, Li-Huan, Li, Xuan, Yang, Dong, Peng, Xiao-Dan, Feng, Gong-Kan, Tang, Jun, Zhu, Xiao-Feng, Deng, Rong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.07.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 13/51; 14/19; 38/109; 38/23; 38/35; 38/88; 38/89; 631/67/1347; 631/67/580/1884; 64/60; 82/58; 82/80; Anticancer properties; Autophagy; Biocompatibility; Breast cancer; CD8 antigen; Cell activation; Cytotoxicity; Degradation; Humanities and Social Sciences; Immune checkpoint inhibitors; Immunosuppression; Immunotherapy; Lymphocytes; Lymphocytes T; multidisciplinary; PD-1 protein; Phagocytosis; Science; Science (multidisciplinary); Skp2 protein; Tenascin; Tenascin C; Toxicity; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-17395-y

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 + 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.