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 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.

PPP2R2B downregulation is associated with immune evasion and predicts poor clinical outcomes in triple-negative breast cancer

“…To date, various immunotherapeutic agents have been developed and improved in TNBC patients. Of which, immune checkpoint inhibitors represent particularly attractive, but anti-PD-1 or anti-PD-L1 antibody alone remains low response rate among TNBC patients [ 9 ]. This was partially attributed to immune suppression of anti-tumor T lymphocytes [ 9 ].…”

“…Of which, immune checkpoint inhibitors represent particularly attractive, but anti-PD-1 or anti-PD-L1 antibody alone remains low response rate among TNBC patients [ 9 ]. This was partially attributed to immune suppression of anti-tumor T lymphocytes [ 9 ]. Additionally, previous reports indicated that elevated TILs levels are frequently associated with a lower risk of relapse and improved survival time in TNBC patients [ 3 , 6 ].…”

“…Compared to other breast cancer subtypes, TNBC could harbor greater potential in immunotherapy due to higher levels of tumor infiltrating lymphocytes (TILs), programmed death-ligand protein (PD-L1), and nonsynonymous mutations [ 7 , 8 ]. However, the recurrence and metastasis of TNBC are frequently facilitated by immune evasion, which is partly due to the restriction of anti-tumor immunity derived by T-lymphocyte in the tumor microenvironment [ 9 ].…”

The Role of Autophagy in Tumor Immunology—Complex Mechanisms That May Be Explored Therapeutically

“…Along with that, autophagy-deficient 4T1 cells, through Atg5 or Beclin1 depletion with specific single guide(sg)RNA, generated larger tumors with reduced CD4 + and CD8 + TILs and IFNg + T cells in Balb/c mice, when compared to autophagy competent 4T1 cells. Moreover, the antitumor effect of the anti-PD1 antibody was limited in autophagy-deficient tumors, while a significant reduction in tumor volume and increased cytotoxic activity of TILs was observed in the control group (90). Similarly, a combination of anti-PD1 immunotherapy with anti-angiogenic endostatin, Endostar, promoted the activation of autophagy pathway PI3K/AKT/mTOR in LLC-bearing mice.…”

Novel Human Tenascin-C Function-Blocking Camel Single Domain Nanobodies

“…Mammary tumor cells also produced transforming growth factor β1 (TGFβ1), which induced TNC expression in the surrounding stroma ( 25 , 26 ). Due to defective autophagy TNC seems to be highly abundant in triple negative breast cancer ( 27 ). An overview of factors regulating TNC expression is presented in Giblin et al ( 23 ).…”