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

Zhi-Ling Li, Hai-Liang Zhang, Yun Huang, Jun-Hao Huang, Peng Sun, Ning-Ning Zhou, Yu-Hong Chen, Jia Mai, Yan Wang, Yan Yu, Li-Huan Zhou, Xuan Li, Dong Yang, Xiao-Dan Peng, Gong-Kan Feng, Jun Tang (), Xiao-Feng Zhu () and Rong Deng ()
Additional contact information
Zhi-Ling Li: Sun Yat-sen University Cancer Center
Hai-Liang Zhang: Sun Yat-sen University Cancer Center
Yun Huang: Sun Yat-sen University Cancer Center
Jun-Hao Huang: Sun Yat-sen University Cancer Center
Peng Sun: Sun Yat-sen University Cancer Center
Ning-Ning Zhou: Sun Yat-sen University Cancer Center
Yu-Hong Chen: Sun Yat-sen University Cancer Center
Jia Mai: Sun Yat-sen University Cancer Center
Yan Wang: Sun Yat-sen University Cancer Center
Yan Yu: Sun Yat-sen University Cancer Center
Li-Huan Zhou: Sun Yat-sen University Cancer Center
Xuan Li: Sun Yat-sen University Cancer Center
Dong Yang: Sun Yat-sen University Cancer Center
Xiao-Dan Peng: Sun Yat-sen University Cancer Center
Gong-Kan Feng: Sun Yat-sen University Cancer Center
Jun Tang: Sun Yat-sen University Cancer Center
Xiao-Feng Zhu: Sun Yat-sen University Cancer Center
Rong Deng: Sun Yat-sen University Cancer Center

Nature Communications, 2020, vol. 11, issue 1, 1-19

Abstract: 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+ 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.

Date: 2020
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DOI: 10.1038/s41467-020-17395-y

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