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

ABSTRACT: 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.

SUBMITTER: El-Hajjar M

PROVIDER: S-EPMC9931548 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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

El-Hajjar Mikal M Gerhardt Lara L Hong Megan M Y MMY Krishnamoorthy Mithunah M Figueredo Rene R Zheng Xiufen X Koropatnick James J Maleki Vareki Saman S

Molecular therapy : the journal of the American Society of Gene Therapy 20220906 2

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 neu ...[more]

PMID: 36068918

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Dataset Information

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

Publications

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

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