Author ORCID Identifier

0000-0001-8966-4046

Date of Graduation

12-2021

Document Type

Dissertation (PhD)

Program Affiliation

Immunology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Stephanie S. Watowich

Committee Member

Shao-Cong Sun

Committee Member

James Allison

Committee Member

Gregory Lizee

Committee Member

Danielle Garsin

Committee Member

Gheath Alatrash

Abstract

Conventional dendritic cells (cDCs) are an essential immune population, responsible for controlling adaptive immunity and tolerance. Recently, type I cDCs (cDC1s) have been delineated as a distinct cDC subset, uniquely responsible for coordinating T cell-mediated immunity against pathogens and tumors. Although the importance of cDC1s is now well established, the mechanisms that regulate cDC1 function remain largely unknown. Signal Transducer and Activator of Transcription 3 (STAT3) mediates the intracellular signaling of interleukin 10 (IL-10), an immunosuppressive cytokine. Therefore, we hypothesized that STAT3 and IL-10 inhibit cDC1 function and induction of T cell-mediated immunity. Herein, we show that IL-10 inhibits polyinosinic:polycytidylic acid (poly I:C)-induced cDC1 maturation in a STAT3-dependent manner. Transcriptome analyses further revealed that although poly I:C induces numerous inflammatory pathways in cDC1s, interferon (IFN) signaling was selectively inhibited by IL-10 and STAT3. Furthermore, assessment of the relative contribution of each IFN type indicated that type I IFN is the primary target of STAT3-mediated inhibition. To determine the impact of these signaling events on cDC1 induction of T cell-mediated immunity, we utilized a cell-based cDC1 anti-tumor vaccine strategy. STAT3 and IL-10 were found to impede the ability of cDC1 vaccination to restrain tumor growth. In addition, both CD8+ T cell and CD4+ T helper cell responses induced by cDC1 vaccination were inhibited by STAT3. Taken together, we conclude that STAT3 inhibits cDC1-induced anti-tumor immunity and cDC1 type I IFN signaling. As cDC1s are essential for the induction of T cell-mediated immunity, these findings could provide rationale for development of novel immunotherapies for cancer and other immune diseases.

Keywords

Dendritic cells, cDC1s, IFNs, tumor microenvironment, tumor immunology, dendritic cell vaccine, immunosuppression

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