Targeting the TGF-beta pathway of cancer-associated fibroblasts in colorectal cancer metastasis
[eng] Colorectal cancer (CRC) is the second-highest cause for cancer-related mortality worldwide. Patients suffering from CRC generally don’t die from primary tumours but rather from metastasis, for which there are no effective therapies to date. CRC progression has been correlated with the accumula...
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| Tipo de documento: | tese |
| Estado: | Versão publicada |
| Data de publicação: | 2020 |
| País: | España |
| Recursos: | Universidad de Barcelona |
| Repositório: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/178619 |
| Acesso em linha: | https://hdl.handle.net/2445/178619 http://hdl.handle.net/10803/671910 |
| Access Level: | Acceso aberto |
| Palavra-chave: | Oncologia Tumors Metàstasi Càncer colorectal Immunoteràpia Fibroblasts Oncology Metastasis Colorectal cancer Immunotheraphy |
| Resumo: | [eng] Colorectal cancer (CRC) is the second-highest cause for cancer-related mortality worldwide. Patients suffering from CRC generally don’t die from primary tumours but rather from metastasis, for which there are no effective therapies to date. CRC progression has been correlated with the accumulation of mutations in four key signalling pathways: Wnt, MAPK, p53 and TGF-β. However, there are no relevant driver mutations described for CRC metastasis, which is produced primarily in the liver. Instead, main features of the tumour microenvironment (TME), such as T cell infiltration and overall levels of TGF-β, have acquired a prognostic value in CRC patients and can predict metastatic potential. Over the years, a better understanding on the TME has led to designing novel therapies for patients with overt metastatic disease. In the past decade, immunotherapies have represented a revolution in clinical oncology. Of note, antibodies targeting the PD-1/PD-L1 inhibitory pathway have yielded promising results in solid tumours such as melanoma, non-small-cell lung cancer and bladder cancer. Nevertheless, these therapies have failed for the majority of CRC patients, who have immunologically “cold” tumours devoid of cytotoxic T cells. In the first chapter of the present thesis, we have used a novel mouse model for metastatic CRC to describe that T cell exclusion in CRC is driven by TGF-β. By blocking the TGF-β pathway using Galunisertib, an inhibitor of the TGF-β receptor 1, activated T cells were able to infiltrate liver metastasis. Consequently, by combining treatment with Galunisertib and monoclonal antibodies against PD-L1, we were able to cure full-blown liver metastases by unleashing a potent T cell-mediated cytotoxic response. Despite the results obtained in chapter 1, the specific cellular mechanisms of this TGF- β-mediated T cell exclusion needed further elucidation. In this regard, our lab has reported that TGF-β leads to the expression of a gene signature in cancer-associated fibroblasts (CAFs) that predicts relapse in patients, and that CAFs are crucial for CRC tumour survival and metastatic colonisation. Therefore, we asked whether TGF-β- activated CAFs were also responsible for T cell exclusion in liver metastases. The work conducted to tackle this question is divided in two chapters. In chapter 2, we have focused on investigating the biology of CAFs from CRC liver metastases, resulting in the establishment of specific markers to target fibroblasts. Moreover, we have defined two different CAF subpopulations coexisting in CRC liver metastases, one of which could be directly related with T cell exclusion. In chapter 3, we have established a genetic mouse model of CRE-LoxP-mediated recombination to specifically ablate the TGF-β receptor 2 in CAFs from liver metastases. CRE expression was driven by the promoter of Transgelin, a TGF-β target gene expressed in CAFs that strongly correlates with relapse in CRC patients. Abrogation of the TGF-β pathway in CAFs did not alter T cell infiltration in metastases. Nevertheless, combination of genetic ablation of the TGF-β receptor 2 and treatment with blocking antibodies against PD-L1 led to curative responses, strongly suggesting that TGF-β- activated CAFs are crucial for mediating T cell exclusion in metastases and evading checkpoint immunotherapy. |
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