Stat3 Inhibits Type I Interferon Signaling In Type I Conventional Dendritic Cells

<p>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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2021

Authors dc:creator

• Chrisikos, Taylor
• <p>0000-0001-8966-4046</p>

Contributors dc:contributor

• Stephanie S. Watowich
• Shao-Cong Sun
• James Allison

• Dendritic cells
• cDC1s
• IFNs
• tumor microenvironment
• tumor immunology
• dendritic cell vaccine
• immunosuppression
• Cancer Biology
• Immunity
• Immunotherapy

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1144

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2200