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TAP1: The Key to Immune Evasion by Breast Cancer Stem Cells?

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Review of “Epigenetic silencing of TAP1 in Aldefluor+ breast cancer stem cells contributes to their enhanced immune evasion” from STEM CELLS by Stuart P. Atkinson

Understanding how cancer stem cells (CSCs) avoid detection and destruction by the immune system may permit the development of new and enhanced anti-cancer therapies. In breast cancer, a small number of studies have indicated that interactions with innate immune cells promote breast CSC maintenance and self-renewal [1-4]. 

To widen this knowledge base, researchers from the laboratory of Paola Marcato (Dalhousie University, Halifax, Nova Scotia, Canada) employed aldehyde dehydrogenase (ALDH) activity to identify and study CSCs from a spontaneous murine mammary tumor cultivated in various mouse models. In their new STEM CELLS study, Sultan et al. report that the epigenetic silencing of transporter associated with antigen processing (TAP) genes in breast CSCs may play a key role in immune evasion mechanisms [5]. 

Following the inoculation of breast CSCs displaying high levels of ALDH activity (as measured by the Aldefluor assay), the authors discovered immune cell infiltration and lower levels of tumor growth in immunocompetent mice when compared to immunocompromised mice. However, even given this tumor growth restriction, the Aldefluor+ CSC population expanded, suggesting that breast CSCs exhibit inherent resistance mechanisms that lead to decreased detection and destruction by the immune system.

Subsequent comparative gene expression analysis of CSCs uncovered a decrease in the expression of antigen processing and presentation genes (e.g., TAP1 and TAP2) and co-stimulatory molecule genes (e.g., CD80) in Aldefluor+ CSCs, an alteration that decreases the susceptibility of CSCs to immune T cell-mediated attack. Further analyses suggested that for the TAP1 and TAP2 genes, an increase in promoter DNA hypermethylation led to the observed reduction in gene expression. 

Interestingly, analysis of patient tumors and 4T1 murine mammary cancer cells (which harbor a large Aldefluor+ CSC population) painted a similar picture, with Aldefluor+ cells expressing lower levels of TAP and CD80 genes. Importantly, further TAP1 knockdown in 4T1 cells via the expression of short hairpin RNA resulted in increased tumor growth in immunocompetent mice.

Overall, this fascinating study establishes that epigenetic silencing of genes involved in antigen processing, such as TAP1, promotes immune evasion and the survival of Aldefluor+ breast CSCs. The authors suggest that treatment with demethylating agents could sensitize tumors to T cell or checkpoint inhibitor immunotherapy and increase antigen processing that may, in turn, lead to the discovery of new tumor-specific antigens for anti-tumor vaccine development.

For more on immune evasion and new CSC targeting anti-tumor strategies, stay tuned to the Stem Cells Portal!

References

  1. Ames E, Canter RJ, Grossenbacher SK, et al., NK Cells Preferentially Target Tumor Cells with a Cancer Stem Cell Phenotype. The Journal of Immunology 2015;195:4010-4019.
  2. Wang B, Wang Q, Wang Z, et al., Metastatic Consequences of Immune Escape from NK Cell Cytotoxicity by Human Breast Cancer Stem Cells. Cancer Research 2014;74:5746-5757.
  3. Lu H, Clauser KR, Tam WL, et al., A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nature Cell Biology 2014;16:1105.
  4. Okuda H, Kobayashi A, Xia B, et al., Hyaluronan Synthase HAS2 Promotes Tumor Progression in Bone by Stimulating the Interaction of Breast Cancer Stem–Like Cells with Macrophages and Stromal Cells. Cancer Research 2012;72:537-547.
  5. Mohammad S, Dejan V, S. PA, et al., Epigenetic Silencing of TAP1 in Aldefluor+ Breast Cancer Stem Cells Contributes to Their Enhanced Immune Evasion. STEM CELLS 2018;36:641-654.