Advisory Committee Chair
Etty N Benveniste
Advisory Committee Members
Jessy Deshane
Douglus R Hurst
Selvarangan Ponnazhagan
Hongwei Qin
Document Type
Dissertation
Date of Award
2015
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
STAT3 signaling is a major intrinsic pathway for cancer inflammation owing to its frequent activation in malignant cells, and key role in regulating many genes crucial for inflammation in the tumor microenvironment. Persistently activated STAT3 increases tumor cell proliferation, survival, and invasion while suppressing anti-tumor immunity. Suppressor Of Cytokine Signaling (SOCS) proteins are negative regulators of the JAK/STAT pathway, and generally function as tumor suppressors. The absence of SOCS3 in particular leads to heightened activation of the STAT3 transcription factor. In the present study, we demonstrate that genetic deletion of SOCS3 specifically in myeloid cells significantly enhances tumor growth, which correlates with elevated levels of myeloid-derived suppressor cells (MDSC) in the tumor microenvironment, and diminished CD8+ T cell infiltration in tumors. The importance of MDSC in promoting tumor growth is documented by reduced tumor growth upon depletion of MDSC. Furthermore, SOCS3-deficient bone-marrow-derived cells exhibit heightened STAT3 activation and preferentially differentiate into the Gr-1+CD11b+Ly6G+ MDSC phenotype. Importantly, we identify granulocyte-colony stimulating factor (G-CSF) as a critical factor secreted by the tumor microenvironment that promotes development of MDSC via a STAT3-dependent pathway. Abrogation of tumor-derived G-CSF reduces the proliferation and accumulation of Gr-1+CD11b+ MDSC and inhibits tumor growth. These findings highlight the critical function of SOCS3 as a negative regulator of MDSC development and function, via inhibition of STAT3 activation. Utilizing SOCS3/STAT3 expression to predict prostate cancer progression and immune therapy responses (anti PD-L1) will also be discussed.
Recommended Citation
Yu, Hao, "Socs3 Deficiency In Myeloid Cells Promotes Tumor Development" (2015). All ETDs from UAB. 3424.
https://digitalcommons.library.uab.edu/etd-collection/3424