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Author Spotlight: Unlocking Insights into the Immune Cell Landscape of Tumors
Published on: August 18, 2023
Spatial transcriptomic analysis of immune checkpoint blockade response in triple negative breast cancers with
Richard H Mebane1,2, Teia Noel1,2, Nathan Ing1,2
1Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Abstract:
Tertiary lymphoid structures (TLSs) are associated with improved cancer immunotherapy responses. However, TLSs vary in their ability to elicit anticancer immune activity, so it is important to develop databases that allow study of variables that regulate their function. We applied single RNA molecule resolution imaging to longitudinal biopsies taken from women with TLS-enriched triple negative breast cancers prior to therapy, after pembrolizumab and after pembrolizumab plus radiation therapy. We developed a computational framework to align and analyze spatial trajectories between TLSs and tumor beds. Tumors with higher T cell infiltration rates were eradicated after pembrolizumab. In contrast, those with lower malignant cell and T cell interaction rates at baseline showed CXCL9+ macrophage infiltration after pembrolizumab, and infiltration of T cells expressing CXCL9-associated programs prior to cancer cell removal after radiation therapy. This manuscript describes single RNA molecule resolution profiling of breast tumors bearing tertiary lymphoid structures throughout an immunotherapy response.
Insights
Tertiary lymphoid structures (TLSs) enhance immunotherapy response in triple-negative breast cancer. Spatial analysis reveals distinct immune cell dynamics correlating with treatment success, aiding future therapeutic strategies.
Area of Science:
- Immunology
- Oncology
- Computational Biology
Background:
- Tertiary lymphoid structures (TLSs) are crucial for effective cancer immunotherapy.
- Variability in TLS function necessitates understanding regulatory factors.
- Triple-negative breast cancer (TNBC) remains a challenging malignancy for treatment.
Purpose of the Study:
- To investigate the role of TLSs in immunotherapy response in TNBC.
- To analyze spatial and temporal immune cell dynamics within TLSs during treatment.
- To identify biomarkers associated with treatment efficacy.
Main Methods:
- Single RNA molecule resolution imaging of longitudinal tumor biopsies.
- Computational framework for spatial alignment and trajectory analysis of TLSs and tumor beds.
- Analysis of immune cell infiltration and gene expression profiles.
Main Results:
- Tumors with high baseline T cell infiltration showed complete eradication after pembrolizumab.
- Lower baseline malignant cell and T cell interaction predicted CXCL9+ macrophage infiltration post-pembrolizumab.
- Radiation therapy promoted T cell infiltration expressing CXCL9-associated programs prior to tumor cell clearance.
Conclusions:
- TLS composition and spatial organization dynamically influence immunotherapy outcomes in TNBC.
- Specific immune cell infiltration patterns can predict treatment response.
- Integrated spatial and molecular profiling offers insights into TLS function during therapy.
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