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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/219878
Dissecting TGFβ-Driven Resistance to αPD-L1 Therapy in Colorectal Cancer Liver Metastases. Enhanced T Cell Motility and Proliferation for Effective Anti-Tumor Responses
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[eng] Colorectal cancer (CRC), particularly its metastatic forms, poses significant therapeutic challenges, with immune checkpoint blockade (ICB) therapies providing limited benefits to patients whose metastasis lack T cell infiltration. This highlights the need to target mechanisms underlying T cell exclusion to improve clinical outcomes. TGF-β signaling plays a pivotal role in regulating the tumor microenvironment (TME) and promoting immune suppression. Using experimental models of metastatic CRC, we demonstrate how TGF-β inhibition enables immune cell infiltration and enhances the efficacy of ICB therapy. Our findings reveal that TGF-β imposes dual immunosuppressive barriers by preventing the migration of memory-like CD8+ T cells from the periphery into the TME and by directing macrophages to suppress the clonal expansion T cells within metastases. We also observed that while TGF-β signaling drives the formation of a dense, collagen-rich extracellular matrix (ECM), it does not inherently restrict T cell motility within the tumor. Instead, PD-1/PD-L1 interactions primarily regulate T cell movement in the TME. Moreover, our study identifies a key role for TGF-β in instructing tumor-associated macrophages (TAMs) to adopt an immunosuppressive phenotype characterized by SPP1 expression, contributing to immune evasion and metastasis. The TGF-β–SPP1 axis was found to correlate with poor prognosis in CRC patients, emphasizing the therapeutic potential of targeting SPP1+ macrophages to overcome immune suppression. Overall, this study provides novel insights into the mechanisms of TGF-β -mediated immune evasion and highlights the importance of targeting TGF-β signaling in both peripheral T cells and TAMs to improve the efficacy of ICB therapies in metastatic CRC.
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SALVANY CELADES, Maria. Dissecting TGFβ-Driven Resistance to αPD-L1 Therapy in Colorectal Cancer Liver Metastases. Enhanced T Cell Motility and Proliferation for Effective Anti-Tumor Responses. [consulta: 26 de novembre de 2025]. [Disponible a: https://hdl.handle.net/2445/219878]