APOE+ Tumor-Associated Macrophages and CD4-DOCK4 T Cells Reveal Distinct Microenvironmental Features in HER2-Low and
Abstract:
Novel anti-HER2 antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan (T-DXd), have shown efficacy in tumors with varying HER2 expression, including HER2-low and even tumors with minimal HER2 presence. This has sparked interest in the biology underlying the HER2 expression spectrum. Using molecular and multiplexed imaging, we revealed distinct immune and stromal features in treatment-naive, hormone receptor-positive (HR+) HER2-low versus HER2-0 tumors. HER2-0 tumors exhibit inflammatory and tissue remodeling gene signatures, with enrichment of APOE⁺ tumor-associated macrophages (TAMs) and DOCK4⁺ CD4 T cells. In contrast, HER2-low tumors are more immunosuppressed, with elevated cell cycle, metabolic, and estrogen signaling pathways, suggesting increased proliferative activity. These findings underscore key biological differences between HR+ HER2-low and HER2-0 breast cancers, and may inform more tailored therapeutic strategies.
Statement Of Significance:
This study revealed the distinct biological profiles of HR+ HER2-low and HER2-0 breast tumors. HER2-0 tumors exhibit inflammatory and tissue remodeling signatures, whereas HER2-low tumors have elevated cell cycle, metabolic, and estrogen signaling. These insights may help refine therapeutic approaches to improve outcomes for breast cancer patients.
Insights
Distinct biological profiles exist between HER2-low and HER2-0 breast cancers. HER2-0 tumors show inflammation, while HER2-low tumors exhibit higher cell cycle and estrogen signaling, informing tailored therapies.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Novel anti-HER2 antibody-drug conjugates (ADCs) demonstrate efficacy across a spectrum of HER2 expression, including HER2-low and HER2-0 breast cancers.
- This has prompted investigation into the biological differences driving tumor responses within the HER2 expression spectrum.
Purpose of the Study:
- To elucidate the distinct immune and stromal features of hormone receptor-positive (HR+) HER2-low versus HER2-0 breast tumors.
- To identify potential therapeutic targets based on these biological differences.
Main Methods:
- Utilized molecular profiling and multiplexed imaging techniques.
- Analyzed treatment-naive, HR+ breast tumors categorized as HER2-low or HER2-0.
Main Results:
- HER2-0 tumors displayed inflammatory and tissue remodeling gene signatures, with enrichment of APOE+ tumor-associated macrophages (TAMs) and DOCK4+ CD4 T cells.
- HER2-low tumors were characterized by immunosuppression and elevated cell cycle, metabolic, and estrogen signaling pathways, indicating increased proliferative activity.
- Identified significant biological distinctions between HR+ HER2-low and HER2-0 breast cancer subtypes.
Conclusions:
- HR+ HER2-low and HER2-0 breast cancers possess fundamentally different biological characteristics.
- These findings may guide the development of more precise and effective therapeutic strategies for distinct breast cancer subtypes.
