Leukemia's genetic quirks shape immune response, opening new vaccine targets
Researchers found that different genetic mutations in chronic lymphocytic leukemia patients trigger distinct immune cell patterns—a discovery that could enable personalized cancer vaccines. The finding suggests doctors can predict which patients harbor unique tumor antigens, potentially improving treatment outcomes and informing drug development strategy.
Originaltitel: T cell receptor gene repertoire profiles in subgroups of patients with chronic lymphocytic leukemia bearing distinct genomic aberrations
<p><strong>Background:</strong> Microenvironmental interactions of the malignant clone with T cells are critical throughout the natural history of chronic lymphocytic leukemia (CLL). Indeed, clonal expansions of T cells and shared clonotypes exist between different CLL patients, strongly implying clonal selection by antigens. Moreover, immunogenic neoepitopes have been isolated from the clonotypic B cell receptor immunoglobulin sequences, offering a rationale for immunotherapeutic approaches. Here, we interrogated the T cell receptor (TR) gene repertoire of CLL patients with different genomic aberration profiles aiming to identify unique signatures that would point towards an additional source of immunogenic neoepitopes for T cells.</p><p><strong>Experimental design:</strong> TR gene repertoire profiling using next generation sequencing in groups of patients with CLL carrying one of the following copy-number aberrations (CNAs): del(11q), del(17p), del(13q), trisomy 12, or gene mutations in <em>TP53</em> or <em>NOTCH1</em>.</p><p><strong>Results:</strong> Oligoclonal expansions were found in all patients with distinct recurrent genomic aberrations; these were more pronounced in cases bearing CNAs, particularly trisomy 12, rather than gene mutations. Shared clonotypes were found both within and across groups, which appeared to be CLL-biased based on extensive comparisons against TR databases from various entities. Moreover, <em>in silico</em> analysis identified TR clonotypes with high binding affinity to neoepitopes predicted to arise from <em>TP53</em> and <em>NOTCH1</em> mutations.</p><p><strong>Conclusions:</strong> Distinct TR repertoire profiles were identified in groups of patients with CLL bearing different genomic aberrations, alluding to distinct selection processes. Abnormal protein expression and gene dosage effects associated with recurrent genomic aberrations likely represent a relevant source of CLL-specific selecting antigens.</p>