Department of Microbiology and Immunology, Western University, London, ON, Canada; London Regional Cancer Program, Lawson Health Research Institute, London, ON, Canada.
Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.
Mol Ther. 2023 Feb 1;31(2):535-551. doi: 10.1016/j.ymthe.2022.08.025. Epub 2022 Sep 6.
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 T cell dependent, as depletion of these cells abolished the effect. Therefore, a therapeutic strategy involving mismatch repair deficiency-based T cell infiltration of neuroblastoma tumors combined with anti-CTLA4 can serve as a novel T cell-based treatment strategy for neuroblastoma.
免疫检查点阻断可以在高度免疫原性错配修复缺陷肿瘤患者中诱导强烈和持久的反应；然而，这些药物对免疫冷的神经母细胞瘤肿瘤无效。为了建立针对神经母细胞瘤的基于 T 细胞的治疗方法，我们表明 T 细胞和记忆 T 细胞依赖性基因表达与高危神经母细胞瘤患者的生存改善相关。为了刺激抗肿瘤免疫并在神经母细胞瘤肿瘤中重现这种免疫表型，我们使用 CRISPR-Cas9 敲除 MLH1——DNA 错配修复途径中的关键分子——以诱导低免疫原性鼠神经母细胞瘤模型中的错配修复缺陷。诱导的错配修复缺陷增加了促炎基因的表达，并刺激 T 细胞浸润到神经母细胞瘤肿瘤中。与诱导错配修复缺陷的成人癌症不同，神经母细胞瘤肿瘤对抗 PD1 治疗仍无反应。然而，抗 CTLA4 治疗对这些肿瘤非常有效。抗 CTLA4 治疗促进了治愈动物的免疫记忆和 T 细胞表位扩散。从机制上讲，抗 CTLA4 治疗对诱导错配修复缺陷的神经母细胞瘤肿瘤的作用是 CD4 T 细胞依赖性的，因为这些细胞的耗竭消除了这种作用。因此，一种涉及神经母细胞瘤肿瘤的基于错配修复缺陷的 T 细胞浸润与抗 CTLA4 联合的治疗策略可以作为神经母细胞瘤的一种新的基于 T 细胞的治疗策略。
