Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY The loss of endogenous tumor suppressors is an obligatory step in tumor onset and progression, but the underlying mechanisms are elusive and the breadth of their targets mostly unknown. We have now discovered that Parkin, a mitochondria-associated E3 ubiquitin ligase biallelically altered in early-onset Parkinson’s Disease, functions as a novel, dual mode tumor suppressor. This involves inhibition of intrinsic tumor traits of cell motility and metabolism but also reprogramming of an antitumor immune microenvironment. In this pathway, Parkin recruitment to mitochondria “primes” immunogenic cell death, controls the release of Damage- Associated Molecular Pattern (DAMP), and activates kinase cascades for transcription of interferon genes and inflammatory cytokines, independently of mitophagy. The result is enhanced intratumoral infiltration of CD8+ T cells, reduced myeloid immunosuppression, and inhibition of primary and metastatic tumor growth. Because Parkin is epigenetically silenced in all human cancers, dual mode tumor suppression is a universal barrier against malignancy. Therefore, the hypothesis that Parkin tumor suppression bridges mitochondrial activation of interferon signaling to immune reprogramming of the microenvironment can be formulated and will constitute the focus of the present application. Three complementary and multidisciplinary specific aims will elucidate the role of Parkin innate immunity in tumor suppression. In the first specific aim, we will characterize how Parkin “primes” immunogenic cell death, elucidate the role of ER stress and autophagy in mitochondrial necroptosis, and map the cellular and biochemical requirements of DAMP release. The second specific aim will dissect the signaling requirements of Parkin activation of innate immunity with respect to cytosolic cGAS-STING and inflammasome activation, mitochondrial RIG-I-MAVS sensing and assembly of a STAT1-regulated ISGF3 transcriptional complex for T cell activation and dendritic cell function. In the third specific aim, we will test the impact of Parkin innate immunity in preclinical orthotopic and transgenic models of primary and metastatic tumor growth, in vivo, modulation of antitumor vaccination strategies, and differential sensitivity to conventional and immune therapies. The application builds on expansive preliminary data, a novel concept of dual mode Parkin tumor suppression, and the redirection of mitochondrial innate immunity, previously known in viral infections, for antitumor responses. The results may be practice changing. As proposed here, the elucidation of Parkin innate immunity will identify new strategies to restore an antitumor immune microenvironment, dampen myeloid immunosuppression and enable broader, more durable patient responses to conventional and immune therapy, including in late-stage disease.
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