OXIDATIVE PHOSPHORYLATION IN MELANOMA BRAIN METASTASES: A REGULATOR of THE TUMOR IMMUNE LANDSCAPE

<p>Previously, we demonstrated via RNA-sequencing analysis of murine intracranial melanoma tumors that pharmacologic inhibition of oxidative phosphorylation (OXPHOS) results in increased expression of genes consistent with activated anti-tumor immune responses. <strong>The central hypothesis of this dissertation is that OXPHOS plays a critical role in the pathogenesis and immune regulation of melanoma brain metastases (MBMs).</strong></p> <p><strong> </strong>The functional significance of OXPHOS was assessed through genetic inhibition, involving knockout (KO) of key regulatory genes such as <em>Ppargc1a </em>(PGC1a) and <em>Ndfus4 </em>(NDUFS4), a component of mitochondrial complex I. PGC1a KO in an RCAS-TVA mouse model of autochthonous lung and brain tumors developing from primary melanomas significantly reduced the incidence of lung and brain tumor formation. Further characterization of OXPHOS at later stages of metastasis (circulation and growth in the metastatic niche) was evaluated using murine melanoma tumors. NDUFS4 KO resulted in decreased tumor burden in the lungs and brain, however there was no impact on incidence of tumor formation in this model, underscoring the critical role of OXPHOS specifically in early tumorigenesis and metastasis formation.</p> <p> Multiplex cytokine analysis of tissue culture supernatants of Wildtype (WT) and NDUFS4 KO murine melanoma cells identified increased secretion of anti-tumor cytokines after OXPHOS inhibition. Multiplex flow cytometry analysis of tumor-infiltrating lymphocytes from intracranial WT and NDUFS4 KO murine melanoma tumors further demonstrated that tumor OXPHOS results in less activated CD4+ T cells. Single cell RNAseq analysis of intracranial WT and NDUFS4 KO murine melanoma tumors indicated that OXPHOS inhibition results in increased levels of adaptive and innate immune cell subsets. Treatment of mice bearing concurrent subcutaneous and intracranial murine melanoma WT or NDUFS4 KO tumors with anti-PD1 and anti-LAG3 demonstrated the most significant increase in overall survival when immunotherapy treatment was combined with OXPHOS inhibition.</p> <p> Together, these findings highlight the significance of tumor OXPHOS in modulating metastatic melanoma progression and the MBM immune microenvironment. Melanoma OXPHOS at early stages of tumorigenesis impacts incidence of MBM and plays a crucial role in immune cell signaling and activation. Further, these studies highlight the potential of melanoma OXPHOS as a therapeutic target to enhance response to checkpoint immunotherapy in MBMs.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2024

Authors dc:creator

• Guerrieri, Renato A
• <p>0000-0003-4762-4905</p>

Contributors dc:contributor

• Michael A. Davies, M.D., Ph.D.
• Michael A. Curran, Ph.D.
• Yon Son (Betty) Kim, M.D., Ph.D.

• melanoma
• brain metastasis
• CNS tumors
• tumor immunology
• oxidative phosphorylation
• OXPHOS
• Cancer Biology
• Immunotherapy

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1373

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2428