Inducing mismatch repair deficiency sensitizes immune-cold neuroblastoma to anti-CTLA4 and generates broad anti-tumor immune memory

• Published in: Molecular therapy 2023-02, Vol.31 (2), p.535-551
• Main Authors: El-Hajjar, Mikal, Gerhardt, Lara, Hong, Megan M Y, Krishnamoorthy, Mithunah, Figueredo, Rene, Zheng, Xiufen, Koropatnick, James, Maleki Vareki, Saman
• Format: Article
• Language: English
• Subjects: Animals; anti-CTLA4; anti-PD1; anti-tumor immunity; Brain Neoplasms; Colorectal Neoplasms - pathology; immune checkpoint blockade; Immunologic Memory; immunological memory; Mice; MMR deficiency; neuroblastoma; Neuroblastoma - genetics; Neuroblastoma - therapy; Original; T cells
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2022.08.025

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. [Display omitted] Poorly immunogenic neuroblastoma tumors that are refractory to immune checkpoint inhibitors can be sensitized to anti-CTLA4 with induced mismatch repair (MMR) deficiency leading to the establishment of broad immunological memory. Induced MMR deficiency and anti-CTLA4 combination therapy may serve as a novel T cell-based therapy for recurrent high-risk neuroblastoma patients.