Pan-cancer multi-omic integration of Trop2 reveals biological determinants and translational implications for ADC

Giulia Notini1,2,3,4,5, Barbara Galbardi1, Giulia Viale1,2

  • 1Medical Oncology Department, IRCCS San Raffaele Hospital, Milan, Italy.

Insights

Trop2 antibody-drug conjugates (ADCs) target epithelial cancers. This study reveals TACSTD2 expression is epigenetically controlled and linked to tumor microenvironment, but antigen levels alone don't predict ADC success.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genomics

Background:

  • Trop2-directed antibody-drug conjugates (ADCs) demonstrate efficacy in epithelial cancers.
  • Understanding Trop2 (TACSTD2) expression determinants is crucial for optimizing ADC therapy.

Purpose of the Study:

  • To comprehensively map TACSTD2 expression, regulation, and functional associations in solid tumors and normal tissues.
  • To investigate the relationship between TACSTD2 expression and factors influencing ADC efficacy and toxicity.

Main Methods:

  • Integrated analysis of bulk and single-cell transcriptomic data from over 20,000 samples (TCGA, GTEx, public atlases).
  • Exploration of genomic alterations, DNA methylation, and co-expression networks related to TACSTD2.

Main Results:

  • TACSTD2 expression is restricted to epithelial cells, enriched in tumors, and epigenetically regulated by DNA methylation.
  • Expression correlates with tumor microenvironment pathways, including barrier integrity and immune interactions.
  • Modest, context-dependent co-expression with ADC-processing and payload sensitivity genes was observed.

Conclusions:

  • Epigenetic factors, not just genomic alterations, predominantly control TACSTD2 expression.
  • TACSTD2 expression influences tumor microenvironment and immune responses, suggesting potential for combination therapies.
  • Tumor antigen abundance alone is insufficient to predict the efficacy or toxicity of Trop2-directed ADCs across different cancer types.

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