Preventing follicular lymphoma progression and transformation through precision therapy

摘要 滤泡性淋巴瘤（FL）是生发中心（GC）B细胞衍生的生长缓慢的肿瘤。虽然最初 无痛性，FL基本上是不可治愈的，许多病例在治疗期间经历进展和复发过程。 他们对治疗的抵抗力越来越强此外，多达45%的病例接受组织学检查， 在某些实施方案中，B细胞淋巴瘤可转化为侵袭性形式的B细胞淋巴瘤，其通常对化学免疫疗法难治。 因此，仍然有一个关键的未满足的需要，以了解如何生存和维持低级别的FL， 制定合理的治疗方案，能够防止疾病的进展和转化， 这些肿瘤。FL的遗传标志包括BCL 2易位和表观遗传学的体细胞突变。 修饰基因如EZH 2。在组织学上，FL通常具有丰富的微环境，最显著的是 具有广泛的滤泡树突细胞（FDC）网络，树突与 淋巴瘤细胞在最近的工作中，我们发现EZH 2功能获得性突变在GC B细胞中的主要作用是 是使他们能够减少对T细胞帮助的依赖，并加强他们的免疫突触形成， FDC诱导GC中心细胞的异常增殖和存活，从而形成FL及其受体。 独特的淋巴瘤免疫生态位值得注意的是，即使GC B细胞是高度T细胞 依赖性FL通常对T细胞增强疗法如检查点抑制剂具有抗性。EZH2 突变的GC B细胞不需要T细胞的帮助，并且不能与T细胞形成稳定的相互作用， 否则抑制这些肿瘤（这可能解释检查点抑制剂失败）。然而，我们发现EZH 2 抑制剂可以招募CD 4和CD 8细胞回到这些淋巴瘤中，我们认为这可能代表了主要的 这种现已获得FDA批准的治疗FL的抗肿瘤机制。此外，我们还表明，EZH 2 抑制剂降低原代人EZH 2突变型淋巴瘤细胞的凋亡阈值， 与BH 3模拟物在体内，并正在实施一项临床试验，结合Tazemetostat和维奈托克治疗FL DLBCL患者。基于这些考虑和其他初步数据，我们假设EZH 2 突变的FL依赖于从FDC接收的信号，最显著的是BAFF受体。我们建议 FDC-FL B细胞免疫突触的治疗靶向将对FL产生致命打击，特别是当 与EZH 2抑制剂组合以恢复T细胞抗淋巴瘤免疫和BH 3模拟物如维奈托克。 我们希望这些治疗可以预防FL的进展和转化。我们提出这项建议的目的是 确定EZH 2突变FL B细胞是否依赖于FDC存活，EZH 2抑制剂是否起作用， 通过恢复FL B细胞与T细胞的相互作用，并利用这些信息来测试新的组合， 预防EZH 2突变型FL进展和向侵袭性FL转化的治疗方法 淋巴瘤

ABSTRACT Follicular lymphomas (FL) are germinal center (GC) B-cell derived, slow-growing tumors. Although initially indolent, FLs are essentially incurable with many cases undergoing progression and a relapsing course during which they become increasingly resistant to therapy. Additionally, as many as 45% of cases undergo histologic transformation to an aggressive form of B-cell lymphoma, that is generally refractory to chemo-immunotherapy. Hence there remains a critical unmet need to understand how low-grade FLs survive and are maintained, and to develop rational therapeutic regimens able to prevent disease progression and transformation and eradicate these tumors. The genetic hallmark of FLs include BCL2 translocations and somatic mutations of epigenetic modifier genes such as EZH2. Histologically, FLs typically feature a rich microenvironment, most notably featuring extensive follicular dendritic cell (FDC) networks with dendrites making extensive contact with lymphoma cells. In recent work we showed that the main effect of EZH2 gain-of-function mutations in GC B-cells is to enable them to become less dependent of T-cell help and strengthen their immune synapse formation with FDCs, which induces aberrant proliferation and survival of GC centrocytes and hence formation of FLs and their unique lymphoma-permissive immune niche. It is notable that even though GC B-cells are highly T-cell dependent, FLs are generally resistant to T-cell augmentation therapies such as checkpoint inhibitors. EZH2 mutant GC B-cells do not require T-cell help and are unable to form stable interactions with T-cells that might otherwise suppress these tumors (which might explain checkpoint inhibitors failure). However, we find that EZH2 inhibitors can recruit CD4 and CD8 cells back into these lymphomas, which we propose may represent the major anti-tumor mechanism of this now FDA-approved treatment in FLs. Moreover we have shown that EZH2 inhibitors reduce apoptotic thresholds in primary human EZH2 mutant lymphoma cells and are highly synergistic with BH3 mimetics in vivo and are implementing a clinical trial combining Tazemetostat and Venetoclax for FL and DLBCL patients. Based on these considerations and other preliminary data we hypothesize that EZH2 mutant FLs are dependent on signals received from FDCs, most notably BAFF receptor. We propose that therapeutic targeting of the FDC-FL B-cell immune synapse will yield a lethal blow to FLs, especially when combined with EZH2 inhibitors to restore T-cell anti-lymphoma immunity and BH3 mimetics such as Venetoclax. We expect these treatments to prevent FL progression and transformation. Our goals for this proposal are to determine whether EZH2 mutant FL B-cells depend on FDCs for their survival, whether EZH2 inhibitors act through restoring interactions of FL B-cells with T-cells, and to leverage this information to test novel combination of therapeutic approaches to prevent progression of EZH2 mutant FLs and transformation to aggressive lymphoma.