Epigenetic Silencing of TAP1 in Aldefluor+ Breast Cancer Stem Cells Contributes to Their Enhanced Immune Evasion

Abstract

Avoiding detection and destruction by immune cells is key for tumor initiation and progression. The important role of cancer stem cells (CSCs) in tumor initiation has been well established, yet their ability to evade immune detection and targeting is only partly understood. To investigate the ability of breast CSCs to evade immune detection, we identified a highly tumorigenic population in a spontaneous murine mammary tumor based on increased aldehyde dehydrogenase activity. We performed tumor growth studies in immunocompetent and immunocompromised mice. In immunocompetent mice, growth of the spontaneous mammary tumor was restricted; however, the Aldefluor population was expanded, suggesting inherent resistance mechanisms. Gene expression analysis of the sorted tumor cells revealed that the Aldefluor tumor cells has decreased expression of transporter associated with antigen processing (TAP) genes and co-stimulatory molecule CD80, which would decrease susceptibility to T cells. Similarly, the Aldefluor population of patient tumors and 4T1 murine mammary cells had decreased expression of TAP and co-stimulatory molecule genes. In contrast, breast CSCs identified by CD44 CD24 do not have decreased expression of these genes, but do have increased expression of C-X-C chemokine receptor type 4. Decitabine treatment and bisulfite pyrosequencing suggests that DNA hypermethylation contributes to decreased TAP gene expression in Aldefluor CSCs. TAP1 knockdown resulted in increased tumor growth of 4T1 cells in immunocompetent mice. Together, this suggests immune evasion mechanisms in breast CSCs are marker specific and epigenetic silencing of TAP1 in Aldefluor breast CSCs contributes to their enhanced survival under immune pressure. Stem Cells 2018;36:641-654.

Induction of immunogenic cell death in radiation-resistant breast cancer stem cells by repurposing anti-alcoholism drug disulfiram

“…BCSCs are resistant to chemotherapy and radiation [2,6,41,43] and recent studies demonstrated that BCSCs escape from innate and adaptive immune responses, which suggests that BCSCs are resistant to immunotherapy as well [44][45][46][47][48]. These findings underscore the importance of developing novel approaches that make BCSCs as sensitive as non-BCSCs to conventional therapies and immunotherapy in order to develop successful and curative treatments for breast cancer patients.…”

ALDH1A3-regulated long non-coding RNA NRAD1 is a potential novel target for triple-negative breast tumors and cancer stem cells

“…Cell analysis and isolation of distinct cell populations using a FACSAria (BD Pharmingen) based on Aldefluor activity (Aldefluor assay kit, StemCell Technologies) was performed as per the manufacturer's instructions and as previously described [36,37]. To remove dead cells from the sorted populations, the cells were stained with 7-AAD.…”

The Flick of a Switch: Conferring Survival Advantage to Breast Cancer Stem Cells Through Metabolic Plasticity

“…Of the breast cancer subtypes, TNBC/basal-like breast cancers have higher percentages of CSCs, which may contribute to their aggressiveness and the worse patient outcomes associated with these breast cancers (17)(18)(19)(20)(21)(22)(23). In terms of mitigating the risk of recurrence, the resistance of CSCs to chemotherapies, radiotherapy, and possibly immunotherapies is an increasing concern (24)(25)(26)(27)(28)(29). Therapies that target CSCs may reduce the risk of relapse.…”