Integrative approach to identify genomic features that shape the immune landscape and predict immunotherapy response in diffuse large B cell lymphoma

项目摘要 复发性/难治性弥漫性大B细胞淋巴瘤（DLBCL）患者的结局仍然很差， 最近的治疗进展，特别是在免疫治疗领域。实体瘤的分类 通过批量转录谱分析，将微环境作为免疫“发炎”或“非发炎”， 检查点阻断疗法（CBT）应答的亚组。相反，DLBCL免疫格局具有 没有得到很好的表征，以及免疫环境特征可以预测的程度， DLBCL患者中的免疫治疗应答是未知的。鉴于越来越多的免疫疗法 在复发性/难治性DLBCL空间中进行探索，更深入地了解DLBCL免疫 景观可能会发现有助于识别可能受益于检查点封锁的患者的线索，和/或 CAR T细胞疗法。此外，越来越多的证据表明，癌细胞内在的改变可以 深刻地影响肿瘤免疫环境，这直接影响免疫疗法的敏感性。如何 恶性B细胞中反复出现的遗传改变和相关通路有助于形成DLBCL 免疫环境尚不清楚。显然需要进行更多的研究，以解决这些差距， 知识为此，我们将策划的免疫和细胞起源（COO）相关基因集整合到 对874例DLBCL标本的转录组进行基因集变异分析（GSVA）。在这四个集群中， 出现（生发中心B细胞（GCB）热，GCB冷，活化B细胞（ABC）热，和ABC冷），分析 的全外显子组测序数据显示，在每个显着丰富的遗传变异。例如，损失- SOCS 1（JAK/STAT信号的负调节因子）中的功能缺失（LOF）突变在GCB中富集。 DLBCL，这表明这些淋巴瘤可能对IFNγ信号特别敏感，并且易受抗-IFN γ抗体的影响。 PD-1治疗。相反，调节磷脂酰丝氨酸（PS）方向的TMEM 30 A中的LOF改变 在ABC冷DLBCL中常见，这可能使这些淋巴瘤 对增强巨噬细胞吞噬作用的免疫疗法敏感。这些观点支持中央 假设淋巴瘤细胞内在机制显著有助于形成独特DLBCL免疫 环境，其特征将确定将或不会从CBT或CAR T中受益的患者 细胞疗法该提案的主要目标是：1）确定选择遗传的机制， 淋巴瘤细胞的改变塑造了DLBCL免疫环境，以及2）发展DLBCL“免疫环境”。 评分”，并确定其在识别将接受PD-1阻断或CAR T细胞治疗的患者中的效用。 有效主要研究者，一位具有淋巴瘤临床专业知识的医生兼科学家， 癌症免疫学背景，非常适合监督本申请中提出的实验。在 为了执行该提案的计算方面，首席研究员招募了一位冉冉升起的星星， 外地他们的互补技能将共同确保成功完成计划的研究。

PROJECT SUMMARY Outcomes for patients with relapsed/refractory diffuse large B cell lymphoma (DLBCL) remain poor despite recent therapeutic advances, particularly in the area of immunotherapy. Classification of solid tumor microenvironments as immune “inflamed” or “non-inflamed” through bulk transcriptional profiling enriches for a subset that is checkpoint blockade therapy (CBT) responsive. Conversely, the DLBCL immune landscape has not been as well-characterized, and the extent to which immune environmental features can predict for immunotherapy response in DLBCL patients is unknown. Given that a growing number of immunotherapies are being explored in the relapsed/refractory DLBCL space, a deeper understanding of the DLBCL immune landscape might uncover clues that aid in identifying patients likely to benefit from checkpoint blockade and/or CAR T cell therapies. Additionally, growing evidence indicates that cancer cell-intrinsic alterations can profoundly affect the tumor immune environment, which directly impacts immunotherapy sensitivity. How recurring genetic alterations and related pathways in malignant B cells contribute to shaping the DLBCL immune environment is unclear. Additional research is clearly needed in order to address these gaps in knowledge. Toward that end, we incorporated curated immune- and cell-of-origin (COO)-related gene sets into a gene set variation analysis (GSVA) on transcriptomes of 874 DLBCL specimens. Among the four clusters that emerged (germinal center B cell (GCB) hot, GCB cold, activated B cell (ABC) hot, and ABC cold), analysis of whole exome sequencing data revealed significantly enriched genetic alterations in each. For instance, loss- of-function (LOF) mutations in SOCS1, a negative regulator of JAK/STAT signaling, were enriched in GCB hot DLBCLs, suggesting these lymphomas may be particularly sensitive to IFNγ signaling and vulnerable to anti- PD-1 therapy. Conversely, LOF alterations in TMEM30A, which regulates phosphatidylserine (PS) orientation in the plasma membrane, were common among ABC cold DLBCLs, which may render these lymphomas sensitive to immunotherapies that enhance macrophage phagocytosis. These observations support the central hypothesis that lymphoma cell-intrinsic mechanisms contribute significantly to shaping unique DLBCL immune environments, the characterization of which will identify patients who will or will not benefit from CBT or CAR T cell therapy. The main objectives of the proposal are: 1) to determine mechanisms by which select genetic alterations in lymphoma cells shape the DLBCL immune environment, and 2) to develop a DLBCL “immune score” and determine its utility in identifying patients for whom PD-1 blockade or CAR T cell therapy will be effective. The principal investigator, a physician-scientist with clinical expertise in lymphoma and a research background in cancer immunology, is well-suited to oversee the experiments proposed in this application. In order to execute computational aspects of the proposal, the principal investigator has recruited a rising star in the field. Together, their complementary skills will ensure successful completion of the planned research.