Immune evasive mechanisms in breast cancer micrometastasis
In metastasis, the existence of tumor cells overcoming the immune system during early organ seeding is crucial, yet the dynamics of tumor-immune interactions during micrometastasis remain unclear. Identifying the vulnerabilities of micrometastases before outbreaking into macrometastases can change t...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/693613 |
| Acceso en línea: | http://hdl.handle.net/10803/693613 |
| Access Level: | acceso embargado |
| Palabra clave: | Micrometastasis Cancer immunoediting Breast cancer TIM3 Immune evasion Immunoedició del càncer Càncer de mama Immunoevasió 616 |
| Sumario: | In metastasis, the existence of tumor cells overcoming the immune system during early organ seeding is crucial, yet the dynamics of tumor-immune interactions during micrometastasis remain unclear. Identifying the vulnerabilities of micrometastases before outbreaking into macrometastases can change therapeutic opportunities for metastasis. Here, we report a novel function of TIM3 in tumor cells, leading micrometastasis survival and immune-escape. Examining the immune selective pressure in breast cancer (BC) metastasis mouse models, we unexpectedly found TIM3 among the most upregulated genes in metastatic surviving BC cells. The selection of TIM3+ tumor cells, is specifically occurring during early seeding of micrometastasis, escaping the immune attack and acquiring stemness. Single-cell RNA-seq of CD45+ immune cells revealed reprogramming of immunosuppressive γδ T cells in TIM3+ micrometastasis, licensing the immune escape metastatic outbreak. Mechanistically, TIM3 loss led to reduced b-catenin signaling in tumor cells, diminishing aggressiveness. Clinical data confirmed increased TIM3+ tumor cells in BC metastasis, and the presence of TIM3+ tumor cells conferred high risk of relapse and poor survival in BC patients. TIM3 blockade therapy reduced the metastatic seeding and overall metastasis in preclinical models. These findings provide a new understanding of micrometastasis and the potential use of TIM3 blockade therapies in subclinical metastasis. |
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