Date of Award

2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Jose R. Conejo-Garcia

Abstract

Estrogens are pleiotropic steroid hormones with pro- and anti-inflammatory effects that influence autoimmune disease and pregnancy. Both autoimmunity and pregnancy are similar to cancer with regard to the immune system. In established tumors, as is the case in autoimmune disease and pregnancy, the host is exposed to self or allogeneic antigens, which are capable of eliciting immune responses. However, for pregnancies to remain viable, autoimmune disease patients survive, and tumors to persist, the immune system must be at least partially tolerized to these challenges. Therefore, I hypothesize that, just as they appear to influence pregnancy and autoimmunity, estrogens’ ability to mediate inflammation and the resulting immune response is a crucial factor in tumor progression. Clinically, antiestrogens are effective adjuvant therapy in estrogen-dependent, receptor (ER) positive breast cancer; however, little is known about their potential role in cancers that are not thought to be estrogen-dependent, such as ovarian cancer. Outside of its direct proliferative effect in ER+ breast tumors, little is known about the effect of estrogen signaling on the tumor microenvironment, despite normal cell ER positivity in a variety of tumors. Using immunocompetent mouse models, we demonstrate that systemic estrogen levels have an important effect on antitumor immunity. Independent of neoplastic cell signaling, estrogens promote tumor progression by directly and indirectly suppressing antitumor T cell responses. Estrogen-driven decreases in antitumor T cell effector activity correspond with a large, cell-intrinsic increase in monocytic and granulocytic myeloid-derived suppressor cells (MDSCs). We show that estrogen signaling increases responsiveness to tumor-initiated inflammatory signals to augment STAT3 activation during myeloid cell differentiation. Estrogen increases the expression of activating kinases, such as Jak2, in bone marrow progenitor cells thus priming the host to respond to tumor-driven IL-6 by producing more MDSCs. Without estrogen signaling, MDSC differentiation and suppressive activity is greatly diminished. Therefore, estrogens are able to play an important role in potentiating a suppressive ovarian tumor microenvironment. This work suggests that antiestrogens have clinical potential in a wide variety of tumors, especially in combination with immunotherapies or chemotherapies targeting pathways critical for MDSC differentiation.

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