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Biological Sciences

(365) Investigation of LAG3 and PD1 in Melanoma Through Integrative Analysis of TCGA and GEO data

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Trainee Category: Graduate Student

    Primary Author(s)

  • ML

    Min Rou Lin

    Ph.D. student
    Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan, Taipei, Taiwan (Republic of China)

    • Co-Author(s)

  • YH

    Yu Wen Hsu

    Ph.D. student
    College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan, Taipei, Taiwan (Republic of China)

  • WC

    Wei Chiao Chang

    Professor
    Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan, Taipei, Taiwan (Republic of China)

    • Trainee Competition Judge(s)

  • Noa Valcarcel, PhD

    Instructional Assistant Professor
    The University of Mississippi

  • PB

    Penni Black

    Associate Professor
    University of Kentucky

  • FA

    FELIX AMISSAH

    Associate Professor of Pharmacology
    Ferris State University
    BIG RAPIDS, Michigan, United States

Objective : Lymphocyte activation gene-3 (LAG3) has become a promising therapeutic target in cancer immunotherapy. This study aims to determine the synergistic effect of anti-LAG3 and anti-PD1 against melanoma and identify new potential targets for melanoma treatment.

Methods: In this study, the role of LAG3 and PD1 in melanoma was investigated via an integrative analysis of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) data. The impact of LAG3 and PD1 expression levels on melanoma clinical manifestations, survival rates, and anti-PD1 treatment response were investigated. Differentially expressed genes (DEGs) enriched with LAG3 were selected for pathway analysis to understand LAG3 biological function and provide new insights for immunotherapy drug development. R version 4.0.2 was used for all statistical analyses.

Results: LAG3 and PD1 expression was strongly correlated (r2=0.91 in TCGA, r2=0.75 in GEO datasets). LAG3 expression was associated with tumor invasion (p=0.00991) and tumor site (p=0.000202). Melanoma patients with high expression levels of LAG3 and PD1 have better overall survival rate, and the benefit was more significant in LAG3+PD1 co-over-expression patients (p=0.0000422). Pathway analysis showed that DEGs enriched with LAG3 were mainly involved in T cell activation, proliferation and differentiation. Moreover, twelve DEGs were enriched in the primary immunodeficiency pathway. We further prioritized IL2RG and JAK3 as potential prognostic markers. Importantly, patients with PD1+LAG3+JAK3+IL2RG co-over-expression were more likely to respond to anti-PD1 therapy compared to patients with PD1 over-expression alone (p=0.0092).

Conclusions: Our study supports the immune checkpoint blockade of anti-PD1 plus anti-LAG3 combination strategy as a treatment option for melanoma patients and highlights IL2RG and JAK3 as new therapeutic targets for preclinical investigation.