Investigating DUSP5 as a modulator of cancer immunity in triple negative breast cancer

Resistance to immunotherapy in triple negative breast cancer (TNBC) is a major barrier to durable responses. There are no robust biomarkers to identify tumors that are intrinsically resistant. Epigenetic repression such as methylation is an important player in resistance. Dr Al-Muftah’ in silico analysis identified DUSP5, a nuclear phosphatase, as significantly hyper-methylated in TNBC. DUSP5 is significantly associated with immune signatures and predictors of response to immunotherapy in TNBC, significantly down-regulated in immune-cold TNBC subtypes and enriched for ERK and cell death pathways. As ERK regulates interferon signaling, which is important for immune regulation and apoptosis, we hypothesis that DUSP5 acts as an immune regulator in TNBC and that it may potentially sensitize tumors to immunotherapy and cell death. The project aims to characterize the role of DUSP5 in immune regulation and investigate whether it modulates susceptibility to immunotherapy in TNBC. The proposal aims to functionally characterize DUSP5 in C.elegans as a system to mechanistically understand its molecular function and role in apoptosis. Bioinformatics, in vitro and in vivo functional and mechanistic validations will be leveraged bridging discovery to translational research. This has the potential for the development of new predictive biomarker for patients’ stratification for immunotherapy or sensitization strategies to enhance the efficacy of immunotherapy in TNBC.

Hamad Bin Khalifa University (HBKU)