To enhance immune control of high-risk, low-TMB neuroblastoma, El-Hajjar et al. showed a positive correlation between T cells and survival in humans, and so attempted to induce more T cells by knocking out the MLH1 gene in a neuroblastoma cell line to induce more mutations via mismatch repair deficiency (iMMRd). iMMRd cells grew more slowly in immunocompetent mice, but tumor control was not further enhanced by anti-PD-1 treatment, which paradoxically increased PD-1 and other inhibitory receptors on CD8+ T cells. Anti-CTLA-4, however, enhanced tumor control, dependent on CD4+ T cells, and generated immunological memory and epitope spreading.
Contributed by Ed Fritsch
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.
Author Info: (1) Department of Microbiology and Immunology, Western University; London, Ontario, Canada; London Regional Cancer Program, Lawson Health Research Institute; London, Ontario, Canad
Author Info: (1) Department of Microbiology and Immunology, Western University; London, Ontario, Canada; London Regional Cancer Program, Lawson Health Research Institute; London, Ontario, Canada. (2) Department of Pathology and Laboratory Medicine, Western University; London, Canada. (3) Department of Pathology and Laboratory Medicine, Western University; London, Canada. (4) Department of Pathology and Laboratory Medicine, Western University; London, Canada. (5) Department of Oncology, Western University; London, Ontario, Canada. (6) Department of Microbiology and Immunology, Western University; London, Ontario, Canada; Department of Pathology and Laboratory Medicine, Western University; London, Canada; Department of Oncology, Western University; London, Ontario, Canada; Department of Surgery, Western University; London, Ontario, Canada. (7) Department of Microbiology and Immunology, Western University; London, Ontario, Canada; Department of Oncology, Western University; London, Ontario, Canada; London Regional Cancer Program, Lawson Health Research Institute; London, Ontario, Canada. (8) Department of Pathology and Laboratory Medicine, Western University; London, Canada; Department of Oncology, Western University; London, Ontario, Canada; London Regional Cancer Program, Lawson Health Research Institute; London, Ontario, Canada. Electronic address: saman.malekivareki@lhsc.on.ca.
