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Date of Award
Doctor of Philosophy (PhD)
Tumors employ multiple mechanisms to evade immune surveillance. One mechanism is tumor-induced myelopoiesis, which expands immune suppressive granulocytes and monocytes to create a protective tumor niche shielding even antigenic tumors. As myeloid cells and immune-stimulatory conventional dendritic cells (cDCs) are derived from the same progenitors, it is logical that tumor-induced myelopoiesis might also impact cDC development. The cDC subset cDC1 is marked by CD141 in humans and CD103 or CD8α in mice. cDC1s act by cross presenting antigen and activating CD8+ T cells. Given these functions, CD103+ cDC1s can support anti-tumor CD8+ T cell responses. However, CD103+ cDC1 numbers are limited within the tumor microenvironment. To understand how CD103+ cDC1s are restricted in the tumor, we investigated their development in the bone marrow (BM). We found that the presence of localized primary tumors resulted in systemic decreases in CD141+ cDC1s in breast and pancreatic cancer patients and animal models. Mechanistically, tumor cell-produced granulocyte stimulating factor (GCSF) mediates the downregulation of the transcription factor interferon regulatory factor 8 (IRF8) in BM progenitors, leading to reduced cellular potential for cDC1 development. Tumor-induced reductions in cDC1-development suppressed the ability of the host to mount anti-tumor CD8+ T cell responses and control tumor growth. Further, BM and systemic decreases in CD141+ cDC1s and their progenitors correlate with patient outcome. Neutralizing GCSF restored cDC1 differentiation and recovered responsiveness to cDC-mediated immunotherapy. These data suggest a new mechanism of immune-escape whereby tumors downregulate cDC1 differentiation from BM progenitors to impair anti-tumor immunity.
Chair and Committee
David G. DeNardo
William E. Gillanders, Kenneth M. Murphy, Sheila A. Stewart, Deborah J. Veis,
Meyer, Melissa Ann, "Tumors Interrupt IRF8-Mediated Dendritic Cell Development to Overcome Immune Surveillance" (2018). Arts & Sciences Electronic Theses and Dissertations. 1562.
Available for download on Wednesday, August 01, 2018