| Autor: |
Mikal El-Hajjar, Lara Gerhardt, Megan M Y Hong, Mithunah Krishnamoorthy, Rene Figueredo, Xiufen Zheng, James Koropatnick, Saman Maleki Vareki |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Molecular Therapy. 31:535-551 |
| ISSN: |
1525-0016 |
| DOI: |
10.1016/j.ymthe.2022.08.025 |
| Popis: |
Immune checkpoint blockade can induce potent and durable responses in patients with highly immunogenic mismatch repair-deficient tumors; however, these drugs are ineffective against immune-cold neuroblastoma tumors. To establish a role for a T cell-based therapy against neuroblastoma, we show that T cell and memory T cell-dependent gene expression are associated with improved survival in high-risk neuroblastoma patients. To stimulate anti-tumor immunity and reproduce this immune phenotype in neuroblastoma tumors, we used CRISPR-Cas9 to knockout MLH1-a crucial molecule in the DNA mismatch repair pathway-to induce mismatch repair deficiency in a poorly immunogenic murine neuroblastoma model. Induced mismatch repair deficiency increased the expression of proinflammatory genes and stimulated T cell infiltration into neuroblastoma tumors. In contrast to adult cancers with induced mismatch repair deficiency, neuroblastoma tumors remained unresponsive to anti-PD1 treatment. However, anti-CTLA4 therapy was highly effective against these tumors. Anti-CTLA4 therapy promoted immune memory and T cell epitope spreading in cured animals. Mechanistically, the effect of anti-CTLA4 therapy against neuroblastoma tumors with induced mismatch repair deficiency is CD4 |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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