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<p>Breast cancer remains the most prevalent cancer among women, with hormone receptor-positive (HR +) tumors accounting for approximately 70% of breast cancer cases. While the immune checkpoint inhibitor (ICI) anti-programmed cell death 1 (PD-1) pembrolizumab has demonstrated efficacy in triple-negative breast cancers (TNBCs), its benefit in HR + subtypes is limited. ICI resistance in breast cancer is largely due to a “cold” tumor immune microenvironment characterized by low tumor-infiltrating lymphocytes (TILs). To identify novel genetic determinants of immune exclusion and pembrolizumab resistance, we analyzed multi-omics and clinical datasets from the I-SPY2 clinical trial and The Cancer Genome Atlas (TCGA), focusing on genes associated with low T cell infiltration and poor response to pembrolizumab. We identified thrombospondin type-1 domain containing 4 (THSD4) as a top candidate. <i>THSD4</i> expression was significantly elevated in breast tumors with low T cells and in breast cancer patients exhibiting resistance to pembrolizumab, particularly within the HR + subtype. <i>THSD4</i> expression is enriched in HR + breast cancers. Validation in local patient cohorts using RNA sequencing and multiplex immunofluorescence confirmed that both high <i>THSD4</i> expression and anti-THSD4 antibody staining correlated with reduced T cell infiltration in the tumor epithelium and associations with poorer clinical outcomes. Functional studies in a syngeneic mouse HR + tumor model demonstrated that THSD4 promotes an immunosuppressive tumor microenvironment, with reduced T cells, resistance to anti-PD-1, and altered collagen fiber abundance. Collectively, these findings establish THSD4 as a prognostic biomarker of pembrolizumab resistance and a potential therapeutic target to enhance immunotherapy efficacy in breast cancer.</p> Graphical abstract <p></p>

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THSD4 is a novel mediator of T cell exclusion and anti-PD-1 resistance in hormone receptor-positive breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月28日

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  • Olivia L. Walker,
  • Marie-Claire D. Wasson,
  • Vishnupriyan Kumar,
  • Sarah Nersesian,
  • Jaganathan Venkatesh,
  • Vishnu V. Vijayan,
  • Lily Coates,
  • Wasundara Fernando,
  • Raj Pranap Arun,
  • Hannah F. Cahill,
  • Elizabeth Baker,
  • Margaret L. Dahn,
  • Drew Slauenwhite,
  • Brianne M. Cruickshank,
  • Penelope Barnes,
  • Modeline N. Longjohn,
  • Thomas James Belbin,
  • Daniel Gaston,
  • Gregory C. Knapp,
  • Jennifer Melvin,
  • Shashi Gujar,
  • Jeanette E. Boudreau,
  • Gillian Bethune,
  • Paola Marcato

摘要

Breast cancer remains the most prevalent cancer among women, with hormone receptor-positive (HR +) tumors accounting for approximately 70% of breast cancer cases. While the immune checkpoint inhibitor (ICI) anti-programmed cell death 1 (PD-1) pembrolizumab has demonstrated efficacy in triple-negative breast cancers (TNBCs), its benefit in HR + subtypes is limited. ICI resistance in breast cancer is largely due to a “cold” tumor immune microenvironment characterized by low tumor-infiltrating lymphocytes (TILs). To identify novel genetic determinants of immune exclusion and pembrolizumab resistance, we analyzed multi-omics and clinical datasets from the I-SPY2 clinical trial and The Cancer Genome Atlas (TCGA), focusing on genes associated with low T cell infiltration and poor response to pembrolizumab. We identified thrombospondin type-1 domain containing 4 (THSD4) as a top candidate. THSD4 expression was significantly elevated in breast tumors with low T cells and in breast cancer patients exhibiting resistance to pembrolizumab, particularly within the HR + subtype. THSD4 expression is enriched in HR + breast cancers. Validation in local patient cohorts using RNA sequencing and multiplex immunofluorescence confirmed that both high THSD4 expression and anti-THSD4 antibody staining correlated with reduced T cell infiltration in the tumor epithelium and associations with poorer clinical outcomes. Functional studies in a syngeneic mouse HR + tumor model demonstrated that THSD4 promotes an immunosuppressive tumor microenvironment, with reduced T cells, resistance to anti-PD-1, and altered collagen fiber abundance. Collectively, these findings establish THSD4 as a prognostic biomarker of pembrolizumab resistance and a potential therapeutic target to enhance immunotherapy efficacy in breast cancer.

Graphical abstract