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Immunological differences between primary and metastatic breast cancer.

B Szekely1, V Bossuyt2, X Li3

  • 1Breast Medical Oncology, Yale Cancer Center, Yale University, New Haven, USA; Department of Oncological Internal Medicine and Clinical Pharmacology "B", National Institute of Oncology, Budapest, Hungary.

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Metastatic breast cancers show a less active immune microenvironment compared to primary tumors, with lower immune cell infiltration and expression of key immunotherapy targets. However, some targets remain, suggesting potential combination therapies.

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Area of Science:

  • Immunology
  • Oncology
  • Translational Research

Background:

  • The immune microenvironment of breast cancer is not well understood during disease progression.
  • Investigating changes in immune cell infiltration and molecular markers is crucial for understanding tumor evolution.

Purpose of the Study:

  • To compare the immune microenvironment between primary and metastatic breast cancer samples.
  • To identify changes in tumor-infiltrating lymphocytes (TILs), programmed death-ligand 1 (PD-L1) expression, and immune-related genes during breast cancer metastasis.

Main Methods:

  • Compared TIL count and PD-L1 protein expression via immunohistochemistry in primary and metastatic breast cancer.
  • Analyzed mRNA levels of 730 immune-related genes using Nanostring technology.
  • Evaluated immune cell metagenes, therapeutic targets, and pathway gene expression.

Main Results:

  • Metastatic tumors had significantly lower TIL counts and PD-L1 positivity compared to primary tumors.
  • Expression of numerous immune cell markers, immuno-oncology targets (e.g., PD1, CTLA4), and immune-activating pathways (e.g., interferon, MHC class I) were significantly downregulated in metastases.
  • Macrophage markers, protumorigenic pathways (e.g., TLR), and complement receptors remained highly expressed in metastases, indicating potential therapeutic targets.

Conclusions:

  • Metastatic breast cancers are immunologically less active than primary tumors.
  • Despite reduced immune activity, preserved expression of certain immune-oncology targets and macrophage/angiogenesis signatures suggests potential for combination immunotherapy strategies.
  • These findings highlight the need for tailored therapeutic approaches for metastatic breast cancer.