Dissecting TGFβ-Driven Resistance to αPD-L1 Therapy in Colorectal Cancer Liver Metastases. Enhanced T Cell Motility and Proliferation for Effective Anti-Tumor Responses
[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 e...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/219878 |
| Acceso en línea: | https://hdl.handle.net/2445/219878 http://hdl.handle.net/10803/694050 |
| Access Level: | acceso abierto |
| Palabra clave: | Càncer colorectal Metàstasi Cèl·lules T Colorectal cancer Metastasis T cells |
| Sumario: | [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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