The Vitamin E Analogue α-TEA Stimulates Tumor Autophagy and Enhances Antigen Cross-Presentation

Abstract

The semi-synthetic vitamin E derivative alpha-tocopheryloxyacetic acid (α-TEA) induces tumor cell apoptosis and may offer a simple adjuvant supplement for cancer therapy if its mechanisms can be better understood. Here we report that α-TEA also triggers tumor cell autophagy and that it improves cross-presentation of tumor antigens to the immune system. α-TEA stimulated both apoptosis and autophagy in murine mammary and lung cancer cells and inhibition of caspase-dependent apoptosis enhanced α-TEA-induced autophagy. Cell exposure to α-TEA generated double membrane-bound vesicles indicative of autophagosomes, which efficiently cross-primed antigen-specific CD8+ T cells. Notably, vaccination with dendritic cells pulsed with α-TEA-generated autophagosomes reduced lung metastases and increased the survival of tumor-bearing mice. Taken together, our findings suggest that both autophagy and apoptosis signaling programs are activated during α-TEA-induced tumor cell killing. We suggest that the ability of α-TEA to stimulate autophagy and enhance cross-priming of CD8+ T cells might be exploited as an adjuvant strategy to improve stimulation of anti-tumor immune responses.

Autophagy in blood cancers: biological role and therapeutic implications

“…34 In particular, studies show how autophagy plays a pivotal role in tumor antigen cross-presentation (priming of CD8 + cytotoxic T cells by soluble antigens/cell-derived materials via antigen presenting cells). 89,90 Interestingly, Ramakrishnan and colleagues found that chemotherapy-induced autophagy may also favor tumor immune rejection by promoting mannose-6-phosphate receptor accumulation at the cancer cell surface. 91 Indeed, mannose-6-phosphate receptor accumulation at the tumor cell surface during chemotherapy was observed in several mouse tumor models and in MM patients.…”

Sorafenib and a novel immune therapy in lung metastasis from hepatocellular carcinoma following hepatectomy: A case report

“…Our studies demonstrated that antigens sequestered in the autophagosome may be delivered to DCs for cross-presentation and prime naïve antigen-specific CD8 T cells effectively (17). Subsequently, autophagosomes containing a broad spectrum of cellular antigens from antigen donor cells were collected by induction of autophagy and inhibition of lysosomal̸proteosomal activity, and named DRibbles (9,14,18,19). DRibbles have been demonstrated to exhibit vigorous antitumor efficacy in mouse experiments and cross-prime human CD8 T cells in ex vivo studies (10,11).…”

Tumor SQSTM1 (p62) expression and T cells in colorectal cancer

“…[11][12][13][14][15] Emerging evidence provides that autophagic activity in tumor cells is essential for promoting cross-presentation of tumor-associated antigens to T cells, indicating a positive link between autophagy and adaptive immunity. [8][9][10][11] On the other hand, autophagy may has an immunosuppressive role, 60 while keeping inverse balance with FOXP3 C cells. These lines of evidence together with our current findings suggest that tumors may choose one or the other for immune evasion.…”

“…However, our specific hypothesis was based on several lines of experimental evidence indicating that autophagic activity in tumor cells promotes antitumor immune response. [8][9][10][11][12][13][14][15][16] Another limitation is that our study used SQSTM1 (but no other biomarkers) to quantify autophagic activity. Future studies should evaluate other autophagic markers including MAP1LC3 (LC3).…”

“…Autophagic activity in tumor cells may enhance extracellular release of immune mediators and cross-presentation of tumor-associated antigens to T cells, thereby potentiating immune response to tumor cells. [6][7][8][9][10][11][12][13][14][15][16][17][18][19] Emerging evidence attests to a key role of tumor autophagic activity in modulating functions of T cells such as CD8…”