Spatial Logic Reconciles Gene-signature Methods in Triple Negative Breast Cancer

Triple-Negative Breast Cancer (TNBC) poses a major clinical challenge due to its diverse nature and limited treatment options, primarily relying on chemotherapy and immunotherapy combinations. Previous attempts to categorize TNBC subtypes based on gene expression profiles have not successfully predicted patient survival or treatment response.

To investigate the role of the tumor microenvironment (TME) and immune cell infiltration in TNBC classification and response variability, we examined the predictive and prognostic abilities of TNBC-type gene signatures and immune cell deconvolution methods within the same datasets. Our findings revealed that immune cell abundance outperformed TNBC subtype signatures, with aggregates of immune cells associated with tertiary lymphoid structures and tumor-associated macrophages/monocytes showing the highest predictive value.

This conclusion was supported in an independent cohort of 67 TNBC patients treated with neoadjuvant chemotherapy. Single-cell RNA sequencing analysis suggested that some of the predictive power of cancer subtype could be attributed to immune and stromal features. Spatial transcriptomic data analysis confirmed the existence of tumor lymphoid structures (TLS) and tumor-associated macrophage/macrophage (TAM) niches within TNBC biopsy samples, which were linked to treatment outcomes.

Our results demonstrate that immune cell aggregates, which capture the spatial organization of the TME, are more effective in predicting TNBC outcomes compared to cell-type specific gene signatures. This novel approach offers a strong framework for understanding spatial relationships in bulk RNA-seq data, providing a potential pathway to integrate past data with emerging spatial profiling technologies.

This work sets the stage for future research to harness the multi-cellular complexity of TNBC, improving diagnostic accuracy and enabling the development of therapies that target the tumor microenvironment for enhanced anti-cancer responses.