AI Insight
This study identified a panel of lectin receptors on tumor-associated macrophages that contribute to immunosuppression in breast cancer. Using patient data from over 3,000 cases and a 3D laboratory model combining cancer cells, fibroblasts, and macrophages, researchers found that targeting the SYK signaling pathway with the inhibitor R406 can reprogram immunosuppressive macrophages to a less tumor-promoting state. The treatment reduced markers of immunosuppression and altered the immune signaling environment within tumors.
Why it matters
The findings identify a potentially druggable target for overcoming immune dysfunction in breast cancer, which could improve responses to immunotherapy. Since SYK inhibitors are already in clinical development for other conditions, this approach could be translated relatively rapidly to improve treatment outcomes in breast cancer patients with immunosuppressive tumor microenvironments.
Understand the Science
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Immunosuppressive tumor microenvironments (TMEs) are common in breast cancer (BC), where tumor-promoting myeloid-driven inflammation contributes to immune dysfunction and poor immunotherapy response. Lectins expressed by tumor-associated macrophages (TAMs) act as glycan-sensing immunoregulatory receptors driving immunosuppression, but whether specific myeloid lectins define immunosuppressive TAM states, or their signaling is pharmacologically targetable remain unclear. We used an orthogonal prioritization approach combining immunosuppressive stratification of the SCAN-B cohort (3207 patients), differential expression, single-cell myeloid localization, and immune-related upstream-regulator inference. Immunosuppressive tumors were enriched for Basal-like and HER2-enriched subtypes, with worse survival. This identified a 12-lectin panel, which was probed in a human 3D immunosuppressive TME model combining BC spheroids, fibroblasts, and blood-derived macrophages under agitation. Flow cytometry confirmed high expression of eight lectins, with four upregulated in TAMs. Survival analyses associated CLEC4E/Mincle, CLEC6A/Dectin-2, and CD209/DC-SIGN with poorer outcomes. As CLEC4E and CLEC6A converge on FcR{gamma}/SYK signaling, this shared node was selected for pathway-level pharmacological perturbation. R406 reduced SYK phosphorylation and induced transcriptional remodeling in TAMs, with attenuation of immunosuppressive macrophage features, reduced CD204/CD206, increased HLA-DR, and remodeling of the soluble-factor profile. These findings define a myeloid lectin framework associated with BC immunosuppression and identify SYK as a candidate targetable node for remodeling TAMs.