Histone 3 K27M mutated (H3K27M+) diffuse midline gliomas (DMGs) are a universally fatal pediatric brain cancer despite recently improved knowledge of the underlying biology. With relatively few advancements in treatment since targeted radiotherapy and a prognosis of generally less than one year to live, children diagnosed with DMGs are in great need of new therapeutic options. Chimeric antigen receptor (CAR) T cells have demonstrated remarkable clinical promise, particularly for blood cancers. To date, potency in solid tumors still remains limited. In preclinical studies, CAR T cells targeting the disialoganglioside GD2 in H3K27M+ DMG mouse models show promising potency, but it remains unclear if patients will have similar success to that seen in the mouse models or if further modifications are necessary. Genome-wide CRISPR/Cas9 screens have identified potentially important mediators of adaptive cellular immunotherapy. Here we assess a putative mechanism of immunological escape in CAR-T cell therapy and test the necessity and sufficiency of the putative mechanism in CAR T cell therapeutic efficacy.