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<p>Recent advances as well as obstacles for immune-based cancer treatment strategies, highlight the notable impact of patient cancer microenvironments on the immune cells and immune targets. Here, we use patient-derived scaffolds (PDS) generated from 110 primary breast cancers to monitor the impact of the cancer microenvironment on immune regulators. Pronounced variation in <i>PD-L1</i> expression is observed in cancer cells adapted to different patient scaffolds. This variation is further linked to clinical observations and correlated with specific proteins detected in the cell-free PDSs using mass spectrometry. When adding T cells to the PDS-based cancer cultures, the killing efficiency of activated T cells vary between the cultures, whereas non-activated T cells modulate the cancer cell <i>PD-L1</i> expression to treatment-predictive values, matching killing capacities of activated T cells. Surviving cancer cells show enrichment in cancer stem cell and epithelial-to-mesenchymal transition (EMT) features, suggesting that T cells may not efficiently target cells with metastatic potential. We conclude that clinically relevant insights in how to optimally target and guide immune-based cancer therapies can be obtained by including patient-derived scaffolds and cues from the cancer microenvironment in cancer patient handling and drug development.</p>

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Breast cancer patient-derived scaffolds enhance the understanding of PD-L1 regulation and T cell cytotoxicity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月16日

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  • Elena Garre,
  • Sara Rhost,
  • Anna Gustafsson,
  • Louis Szeponik,
  • Thais Fenz Araujo,
  • Marianne Quiding-Järbrink,
  • Khalil Helou,
  • Anders Ståhlberg,
  • Göran Landberg

摘要

Recent advances as well as obstacles for immune-based cancer treatment strategies, highlight the notable impact of patient cancer microenvironments on the immune cells and immune targets. Here, we use patient-derived scaffolds (PDS) generated from 110 primary breast cancers to monitor the impact of the cancer microenvironment on immune regulators. Pronounced variation in PD-L1 expression is observed in cancer cells adapted to different patient scaffolds. This variation is further linked to clinical observations and correlated with specific proteins detected in the cell-free PDSs using mass spectrometry. When adding T cells to the PDS-based cancer cultures, the killing efficiency of activated T cells vary between the cultures, whereas non-activated T cells modulate the cancer cell PD-L1 expression to treatment-predictive values, matching killing capacities of activated T cells. Surviving cancer cells show enrichment in cancer stem cell and epithelial-to-mesenchymal transition (EMT) features, suggesting that T cells may not efficiently target cells with metastatic potential. We conclude that clinically relevant insights in how to optimally target and guide immune-based cancer therapies can be obtained by including patient-derived scaffolds and cues from the cancer microenvironment in cancer patient handling and drug development.