Schulte Sara C, Peter Wolfgang, Rosenberger Georg, Schäfer Moritz, Maire Cecile L, Rünger Alessandra, Ryba Alice, Riecken Kristoffer, Fita Krystian D, Matschke Jakob, Akyüz Nuray, Dierlamm Judith, Klau Gunnar W, Ricklefs Franz L, Gempt Jens, Westphal Manfred, Lamszus Katrin, Dilthey Alexander, Mohme Malte
Algorithmic Bioinformatics, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Institute of Medical Microbiology and Hospital Hygiene, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Cancer Immunol Res. 2025 Jul 2;13(7):1111-1123. doi: 10.1158/2326-6066.CIR-24-0419.
Immune evasion is a hallmark of gliomas, yet the genetic mechanisms by which tumors escape immune surveillance remain incompletely understood. In this study, we systematically examined the presence of somatic mutations in HLA genes and genes encoding proteins involved in antigen presentation across isocitrate dehydrogenase wild-type and mutant gliomas using targeted next-generation sequencing. To address the challenges associated with detecting somatic mutations in these highly polymorphic and complex regions of the genome, we applied a combination of short-read and long-read sequencing techniques, extended the genetic region of interest (exons and introns), and applied a tailored bioinformatics analysis pipeline, which enabled an accurate evaluation of comprehensive sequencing data. Our analysis identified mutations in HLA class II and nonclassic HLA genes as well as genes associated with antigen presentation, such as TAP1/2 and B2M. Three-dimensional modeling of individual mutations simulated the potential impact of somatic mutations in TAP1 and B2M on the encoded protein configuration. The presence of somatic mutations supports the role of antigen-presenting genes in the pathophysiology and potential immune escape of gliomas. Our data demonstrated an increased frequency of such mutations in recurrent glioblastoma, potentially resulting from a positive selection or mutagenic enrichment of tumor cells during tumor progression. Taken together, this research generates new insights and hypotheses for the functional analysis and optimization of immunotherapy strategies for gliomas, which may guide personalized treatment paradigms.
免疫逃逸是胶质瘤的一个标志，但肿瘤逃避免疫监视的遗传机制仍未完全了解。在本研究中，我们使用靶向二代测序系统检查了异柠檬酸脱氢酶野生型和突变型胶质瘤中HLA基因以及编码参与抗原呈递的蛋白质的基因中的体细胞突变情况。为应对在基因组这些高度多态和复杂区域检测体细胞突变相关的挑战，我们应用了短读长和长读长测序技术的组合，扩展了感兴趣的遗传区域（外显子和内含子），并应用了定制的生物信息学分析流程，从而能够准确评估全面的测序数据。我们的分析确定了HLA II类和非经典HLA基因以及与抗原呈递相关的基因（如TAP1/2和B2M）中的突变。对单个突变的三维建模模拟了TAP1和B2M中体细胞突变对编码蛋白构象的潜在影响。体细胞突变的存在支持了抗原呈递基因在胶质瘤病理生理学和潜在免疫逃逸中的作用。我们的数据表明，复发性胶质母细胞瘤中此类突变的频率增加，这可能是由于肿瘤进展过程中肿瘤细胞的阳性选择或诱变富集所致。综上所述，本研究为胶质瘤免疫治疗策略的功能分析和优化产生了新的见解和假设，这可能指导个性化治疗模式。
