"REGULATION OF INTERFERON- INDUCED INTERLEUKIN-8 AND PD-L1 EXPRESSION I" by Sveta Padmanabhan

Date of Award

2022

Document Type

Dissertation

Degree Name

Biological Sciences (Ph.D.)

Department

Biological Sciences

First Advisor

Ivana Vancurova

Second Advisor

Ales Vancura

Third Advisor

Matteo Ruggiu

Abstract

Interferon-γ (IFNγ) is a pleiotropic cytokine that has a crucial role in immune response and tumor immunity. Because of its anti-tumor effects, IFNγ has been used in cancer treatment. However, IFNγ also has tumor-promoting functions that are less well understood. Here, I show that IFNγ induces expression of the pro-inflammatory and pro-angiogenic chemokine interleukin-8 (IL-8, CXCL8) in ovarian cancer (OC) cells. The IFNγ-induced IL-8 expression is dependent on JAK1, STAT1, and p65 NFκB, and is associated with an increased occupancy of K314/ 315 acetylated p65 NFκB and Ser-727 phosphorylated STAT1 at the IL-8 promoter. Neutralization of IL-8 using anti-IL-8 antibody reduces IFNγ-induced migration of OC cells. These findings indicate that the IFNγ-induced IL-8 expression contributes to IFNγ pro-tumorigenic effects in ovarian cancer cells. In addition, IFNγ induces expression of immune checkpoint PD-L1 in OC cells, resulting in their increased proliferation and tumor growth, but the mechanisms that regulate PD-L1 expression in OC remain unclear. My results demonstrate that the IFNγ-induced PD-L1 expression in OC cells is associated with increased levels of STAT1, Tyr-701 pSTAT1 and Ser-727 pSTAT1. Suppression of JAK1 and STAT1 significantly decreases the IFNγ-induced PD-L1 expression in OC cells. In addition, IFNγ induces expression of the transcription factor interferon regulatory factor 1 (IRF1) and IRF1 suppression attenuates the IFNγ-induced gene and protein levels of PD-L1. Chromatin immunoprecipitation results show that IFNγ induces PD-L1 promoter acetylation and recruitment of STAT1, Ser-727 pSTAT1 and IRF1 in OC cells. These findings demonstrate that the IFNγ-induced PD-L1 expression in OC cells is regulated by JAK1, STAT1, and IRF1 signaling, and suggest that targeting the JAK1/ STAT1/IRF1 pathway may provide a leverage to regulate the PD-L1 levels in ovarian cancer. Studying the molecular mechanisms that regulate expression of IFNγ-induced IL-8 and PD-L1 will contribute to better understanding of tumor promoting functions of IFNγ

Included in

Biology Commons

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