Leveraging MicroRNA Functions for Enhanced CAR T Cell Efficacy in Pediatric Brain Tumors
Open Access DepositedDiffuse Intrinsic Pontine Glioma (DIPG) is the most lethal pediatric brain cancer, boasting a disheartening 5-year survival rate below 2%. Adoptive immunotherapy using chimeric antigen receptor (CAR) T cells has emerged as a promising avenue, offering the potential for potent and specific immune responses against tumor cells. However, translation of CAR T cell therapy to brain tumors faces substantial impediments, notably tumor heterogeneity and the immunosuppressive tumor microenvironment (TME).MicroRNAs (miRs) are small non-coding RNAs that modulate essential biological processes by regulating gene expression post-transcriptionally. Dysregulated miR expression is a hallmark of DIPG, orchestrating gliomagenesis and reshaping the TME. Additionally, miRs governs T cell immune responses by modulating genes involved in T cell differentiation, proliferation, and activation. Therefore, we hypothesize that targeting dysregulated miR expression in DIPG can potentiate CAR T cell therapy through TME immunomodulation. We performed comprehensive miR profiling of post-mortem DIPG tumors, revealing marked heterogeneity in miR expression across tumors and compared to normal brain. We identified 107 upregulated and 133 downregulated miRs within tumors, correlating with immune pathways, tumor cell migration, invasion, and immune evasion. This dysregulated miR expression was also associated with suppressed immune recruitment, migration, and activation pathways, indicative of a profoundly cold microenvironment. Subsequent analysis in immune-competent mouse models implanted with DIPG tumors also shows heterogeneity in miR expression following CAR T cell treatment correlating with altered myeloid and T cell recruitment and activation. Mice treated with B7H3 CAR T cells showed more robust miR expression fluctuations than the control thus, revealing prominent miRs of interest. Our ongoing efforts now center on investigating miR-mRNA interactions and correlating these interactions with functional data to elucidate underlying mechanisms and identify potential therapeutic targets. The data derived from these endeavors will serve as a pivotal foundation, justifying the clinical exploration of miRs to enhance CAR T cell immunotherapy in DIPG patients. This interdisciplinary approach holds promise in reshaping the therapeutic landscape of DIPG, offering renewed hope for patients and families grappling with this devastating disease.
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