Dados do Trabalho

Título

Unveiling Metabolic Therapeutic Targets for Immune Checkpoint Inhibitor Non-Responsive Melanomas

Introdução

The approval of immune checkpoint inhibitors (ICIs), as nivolumab, pembrolizumab, and atezolizumab, has brought improved outcomes for patients with melanoma. However, some patients don’t achieve a complete response. In tumor cells, the energetic metabolism undergoes reprogramming, with energy primarily obtained through aerobic glycolysis. High glycolytic rates and pro-tumoral cellular activity contribute to the restructuring of a new tumor microenvironment, potentially influencing therapy response.

Objetivo

The aim of the project is to explore the therapeutic potential of targets related to metabolism in melanoma unresponsive to ICIs.

Métodos

For the selection of genes of interest, a functional enrichment analysis and interaction networks were conducted using the STRING software on differentially expressed genes between tumors from responsive and unresponsive to ICI therapy, using the nCounter® Metabolic Pathways Panel (NanoString). The melanoma cell lines A375, SKMEL19, SKMEL28, UACC62, WM35 and WM164 are being assessed for the expression of target proteins through Western Blotting. Afterward, knockdown (KD) of the selected genes will be performed using siRNA, and its effect will be evaluated through analysis of cell viability, glucose and lactate consumption, cell proliferation, colony formation, migration, invasion, and cellular apoptosis.

Resultados

A total of 43 differentially expressed genes were identified between tumors of responsive and unresponsive patients to immunotherapy, with 24 genes overexpressed in unresponsive patients. Based on the highest fold-change, interaction pathways, and functional enrichment analysis, 5 genes were selected from those overexpressed in tumors of unresponsive patients. These genes are involved in amino acid synthesis pathways and glutamine synthesis.

Conclusões

Finally, through the execution of the functional assays, it is anticipated to identify potential therapeutic targets that could be used as therapeutic alternatives for patients with melanomas unresponsive to ICIs.

Palavras-chave

immunometabolism
immunotherapy
melanoma

Financiador do resumo

CAPES