Toward personalized lymphoma immunotherapy: Identification of common driver mutations recognized by patient CD8+ T cells
Menée à l'aide de techniques de séquençage à haut débit sur des échantillons tumoraux prélevés sur 53 patients atteints d'un lymphome folliculaire, cette étude met en évidence la présence de lymphocytes T CD8+ reconnaissant spécifiquement des gènes mutés, notamment CREBBP et MEF2B
Purpose: A fundamental challenge in the era of next-generation sequencing (NGS) is to design effective treatments tailored to the mutational profiles of tumors. Many newly discovered cancer mutations are difficult to target pharmacologically; however, T cell-based therapies may provide a valuable alternative owing to the exquisite sensitivity and specificity of antigen recognition. To explore this concept, we assessed the immunogenicity of a panel of genes that are common sites of driver mutations in follicular lymphoma (FL), an immunologically sensitive yet currently incurable disease. Experimental Design: Exon capture and NGS were used to interrogate tumor samples from 53 FL patients for mutations in 10 frequently mutated genes. For 13 patients, predicted mutant peptides and proteins were evaluated for recognition by autologous peripheral blood T cells after in vitro priming. Results: Mutations were identified in 1-5 genes in 81% (43/53) of tumor samples. Autologous, mutation-specific CD8+ T cells were identified in 23% (3/13) of evaluated cases. T cell responses were directed toward putative driver mutations in CREBBP and MEF2B. Responding T cells showed exquisite specificity for mutant versus wild type proteins and recognized lymphoma cells expressing the appropriate mutations. Responding T cells appeared to be from the naïve repertoire, as they were found at low frequencies and only at single time points in each patient. Conclusions: FL patients harbor rare yet functionally competent CD8+ T cells specific for recurrent mutations. Our results support the concept of using NGS to design individualized immunotherapies targeting common driver mutations in FL and other malignancies.