LAG3

Overview

LAG3 (Lymphocyte Activation Gene 3, CD223) is an inhibitory immune checkpoint receptor expressed on exhausted CD4+ and CD8+ T cells. Together with PDCD1 (PD-1) and HAVCR2 (TIM-3), LAG3 marks progressive T-cell dysfunction in the tumor microenvironment. LAG3 is a clinical target for immune checkpoint blockade.

Alterations observed in the corpus

  • LAG3 progressively upregulated on CD8+ T cells in HGSOC fallopian tube precursor lesions across the progression axis (normal FT → p53 signature → STIC → invasive cancer); LAG3+ CD8+ T cells increase 3- to 7-fold; LAG3+ and PD1+LAG3+ double-positive CD8+ T cells increase from p53.I through STIC.C and cancer, defining exhaustion states. PMID:39386723
  • Approximately 14% of CD4+ T cells in HGSOC precursor specimens expressed LAG3, co-existing with other exhaustion/activation markers (HLA-DR, PD1). PMID:39386723
  • Inhibitory receptor on exhausted T cells; LBL-007 + toripalimab achieved ORR 33.3% in ICI-naïve NPC, and relatlimab + nivolumab is under evaluation in the randomized REMAIN trial PMID:24952746
  • No significant differential expression of LAG3 between anti-PD-1 responders vs non-responders in whole-tumor transcriptome analysis of metastatic melanoma (n=28 RNA-seq) PMID:26997480
  • LAG3 expression increased on-therapy during nivolumab treatment in melanoma patients regardless of response, as part of a broad immune checkpoint gene upregulation signature (also including PDCD1, CD274, CTLA-4, ICOS, and TNFRSF9) PMID:29033130

Cancer types (linked)

  • HGSOC and precursor lesions (STIC): LAG3 is an exhaustion marker progressively upregulated on CD8+ and CD4+ T cells as the disease evolves from early fallopian tube precursors to invasive cancer. Studied in 44 FFPE fallopian tube specimens from 43 patients using CyCIF (31-antibody panel) and GeoMx WTA spatial transcriptomics. PMID:39386723

Co-occurrence and mutual exclusivity

  • Co-upregulated with PDCD1 (PD-1), HAVCR2 (TIM-3), and CTLA4 on CD8+ T cells across HGSOC precursor stages; PD1+LAG3+ double-positive cells represent the most exhausted T-cell compartment. PMID:39386723
  • LAG3 expression on CD4+ T cells co-exists with HLA-DR+ and PD1+ markers, indicating mixed activation/exhaustion states. PMID:39386723

Therapeutic relevance

  • Progressive LAG3 upregulation in HGSOC precursors suggests LAG3 inhibition as a potential strategy for immune interception at early disease stages; however, no LAG3-targeted treatment was administered in this study. PMID:39386723
  • LAG3 co-expression with PD-1 supports the rationale for dual checkpoint blockade (anti-PD-1 + anti-LAG3) in HGSOC, a combination under investigation in clinical trials for ovarian cancer. PMID:39386723

Open questions

  • Whether LAG3 upregulation in HGSOC precursors (STIC) is reversible by immune interception strategies before malignant transformation is unresolved. PMID:39386723
  • The functional consequences of LAG3+/PD-1+ double exhaustion in STIC vs invasive cancer on anti-tumor cytotoxic capacity have not been directly measured. PMID:39386723

Sources

This page was processed by crosslinker on 2026-05-04. - PMID:24952746

This page was processed by wiki-cli on 2026-05-11. - PMID:26997480

This page was processed by wiki-cli on 2026-05-14. - PMID:29033130

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