Hematopoietic stem cell specific V-ATPase controls breast cancer progression and metastasis via cytotoxic T cells
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Manoranjan Sahoo1, Gajendra K. Katara1, Mahmood Y. Bilal1, Safaa A. Ibrahim1, Arpita Kulshrestha1, Sara Fleetwood1, Kimiko Suzue2 and Kenneth D. Beaman1
1Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
2Department of Pathology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
Kenneth D. Beaman, email: [email protected]
Keywords: tumor microenvironment (TME); breast tumor; CD8+ T cells; hematopoietic stem cells (HSC); vacuolar ATPase
Received: July 05, 2018 Accepted: August 13, 2018 Published: September 04, 2018
The interaction of recruited immune effector cells and cancer cells within tumor microenvironment (TME) shapes the fate of cancer progression and metastasis. Many cancers including breast cancer, express a specific vacuolar ATPase (a2V) on their cell surface which acidifies the extracellular milieu helping cancer cell proliferation and metastasis. To understand the role of immune cell-associated-a2V during breast tumor pathogenesis, we knocked-out a2V (KO) from the hematopoietic stem cells (HSC) and generated breast tumors in mice. The a2V-KO mice developed faster growing, larger, and metastatic breast tumors compared to control mice. Further investigation of the TME revealed a significant reduction in the presence of CD4+ and CD8+ T cells in the a2V-KO tumors. Targeted RNA-Seq of the cells of the TME demonstrated that pro-inflammatory cytokines, death receptors, death receptor ligands, and cytotoxic effectors were significantly down-regulated within the a2V-KO TME. Interestingly, analysis of immune cells in the blood, spleen, and thymus of the non-tumor bearing a2V-KO mice revealed a significant decrease in CD4+ and CD8+ T cell populations. For the first time, this study demonstrates that inhibition of V-ATPase expression in HSC leads to a decrease in CD4+ and CD8+ T cell populations and thus promotes breast tumor growth and metastasis.
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