University of Kentucky

Exploring the Role of Inhibiting SHP2 to Enhance Immune Responses to Combat Lung Cancer

Presenter Information

Palak PatelFollow

Grade Level at Time of Presentation

Senior

Major

Biology

Institution 24-25

University of Kentucky

KY House District #

9

KY Senate District #

1

Department

Pharmaceutical Sciences Dept.

Abstract

Lung cancer remains the leading cause of cancer-related deaths in Kentucky, with non-small cell lung cancer (NSCLC) as the most common and deadly subtype. Immune checkpoint inhibitor immunotherapy (ICIs) has transformed treatment by targeting immune checkpoint proteins like programmed death ligand (PD-L1), which normal cells use to evade immune attacks on self. PD-L1 binds to the programmed death protein-1 (PD-1) on T-cells, suppressing their activity, even to fight cancer. ICIs inhibit PD-L1: PD-1 interactions and allow T cells to fight cancer cells. Understanding how PD-L1 is regulated is critical to improving the effectiveness of ICIs and lung cancer outcomes.

Our research investigates the tyrosine phosphatase protein, SHP2, which plays a role in signaling pathways within cancer cells. Previous studies suggested that SHP2 negatively regulates PD-L1 expression. However, our findings show that inhibiting SHP2 phosphatase activity does not directly affect PD-L1 levels. This result led us to hypothesize that SHP2 influences PD-L1 through interactions with other proteins, such as the RNA helicase, DDX3X.

To test this, we used H460 lung cancer cells treated with SGA-01, a compound that degrades SHP2. Our experiments, including protein analysis and gene expression studies, revealed that degrading SHP2 increases PD-L1 protein levels, suggesting a post-transcriptional regulatory mechanism. This finding is one step closer to creating more individualistic and effective immunotherapies.

Future research will examine the impact of independently excising of SHP2 and DDX3X on PD-L1 expression and immune response pathways. By uncovering the mechanisms behind the role of SHP2 in regulating PD-L1, this work aims to identify novel therapeutic targets to enhance ICI, and ultimately, T-cell function. We expect this research to lead to more effective immunotherapy strategies, offering hope to lung cancer patients in Kentucky and beyond.

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Exploring the Role of Inhibiting SHP2 to Enhance Immune Responses to Combat Lung Cancer

Lung cancer remains the leading cause of cancer-related deaths in Kentucky, with non-small cell lung cancer (NSCLC) as the most common and deadly subtype. Immune checkpoint inhibitor immunotherapy (ICIs) has transformed treatment by targeting immune checkpoint proteins like programmed death ligand (PD-L1), which normal cells use to evade immune attacks on self. PD-L1 binds to the programmed death protein-1 (PD-1) on T-cells, suppressing their activity, even to fight cancer. ICIs inhibit PD-L1: PD-1 interactions and allow T cells to fight cancer cells. Understanding how PD-L1 is regulated is critical to improving the effectiveness of ICIs and lung cancer outcomes.

Our research investigates the tyrosine phosphatase protein, SHP2, which plays a role in signaling pathways within cancer cells. Previous studies suggested that SHP2 negatively regulates PD-L1 expression. However, our findings show that inhibiting SHP2 phosphatase activity does not directly affect PD-L1 levels. This result led us to hypothesize that SHP2 influences PD-L1 through interactions with other proteins, such as the RNA helicase, DDX3X.

To test this, we used H460 lung cancer cells treated with SGA-01, a compound that degrades SHP2. Our experiments, including protein analysis and gene expression studies, revealed that degrading SHP2 increases PD-L1 protein levels, suggesting a post-transcriptional regulatory mechanism. This finding is one step closer to creating more individualistic and effective immunotherapies.

Future research will examine the impact of independently excising of SHP2 and DDX3X on PD-L1 expression and immune response pathways. By uncovering the mechanisms behind the role of SHP2 in regulating PD-L1, this work aims to identify novel therapeutic targets to enhance ICI, and ultimately, T-cell function. We expect this research to lead to more effective immunotherapy strategies, offering hope to lung cancer patients in Kentucky and beyond.