The spatial immune landscape predicts outcome and reveals the central role of tumor-associated macrophages in inflammatory breast cancer biology

Background: Inflammatory breast cancer (IBC) is a rare but aggressive subtype of breast cancer characterized by rapid progression and poor prognosis. Despite its distinct clinical presentation and molecular features, the immune landscape of IBC and its potential role in driving the aggressive phenotype remain poorly understood. This study aimed to characterize the spatial immune landscape of IBC, compare it with that of subtype-matched non-inflammatory breast cancer (nIBC), and evaluate the prognostic implications of immune cell composition and localization.

Methods: We analyzed pre-treatment tumor samples from 161 IBC and 115 subtype-matched nIBC patients using immunohistochemistry (IHC) for CD8, FOXP3, CD79α, CD163, and PD-L1. Digital image analysis quantified the immune cell density and relative marker area in the tumor area (TA) and invasive margin (IM). Associations with clinicopathological features, pathological response to neoadjuvant chemotherapy (NACT), and survival were assessed using multivariate logistic regression and Cox proportional hazards models. Transcriptomic validation was performed using Affymetrix gene expression data and consensus TME deconvolution.

Results: IBC showed higher infiltration of CD163 + tumor-associated macrophages (TAMs) compared to nIBC. Gene expression data confirmed IHC findings, and pathway analysis linked high TAM density with inflammatory and proliferative pathways. The spatial distribution of immune cells was prognostically relevant, with high CD8 + T-cell infiltration (OR: 0.41, 95% CI: 0.22–0.76, P = 0.004) and low CD79α + B-cell infiltration (OR: 3.19, 95% CI: 1.68–6.03, P < 0.001) correlating with improved overall survival in IBC. Furthermore, the ratio of CD8+ T-cells to FOXP3+ regulatory T-cells within the TA was a significant prognostic indicator (OR: 0.34, 95% CI: 0.14–0.83, P = 0.018), whereas the absolute densities of either CD8+ or FOXP3 + T-cells alone were not associated with outcome.

Conclusions: These results highlight the immunosuppressive nature of the IBC microenvironment and the role of TAMs in promoting an aggressive IBC phenotype. Spatial context and the balance between the immune cells, rather than the overall abundance, was critical in determining outcome. Our findings underscore the importance of considering immune cell localization in prognostic assessment and support further investigation of TAM-targeted therapies in IBC.