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细胞来源的、生长缓慢的肿瘤。尽管最初 懒惰的FLS基本上是无法治愈的，许多病例在 他们对治疗变得越来越抗拒。此外，多达45%的病例接受了组织学检查 转化为侵袭性的B细胞淋巴瘤，通常对化学免疫治疗无效。 因此，仍有一个关键的需求尚未得到满足，即了解低等级自由贸易是如何生存和维持的，以及 开发合理的治疗方案，防止疾病的进展和转化并根除 这些肿瘤。FLS的遗传特征包括BCL2易位和表观遗传学的体细胞突变 修饰基因，如EZH2。在组织学上，FLS通常具有丰富的微环境，最值得注意的是 以广泛的滤泡树突状细胞(FDC)网络为特征，树突状细胞与 淋巴瘤细胞。在最近的工作中，我们证明了EZH2功能获得突变在GC B细胞中的主要作用 是使他们变得不那么依赖T细胞的帮助，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FLS和FLS。 独特的淋巴瘤-允许免疫利基。值得注意的是，尽管GC B细胞是高度T细胞 依赖的FLS通常对检查点抑制剂等T细胞扩增疗法具有耐药性。EZH2 突变的GC B细胞不需要T细胞的帮助，也不能与T细胞形成稳定的相互作用 否则抑制这些肿瘤(这可能是检查点抑制剂失效的原因)。然而，我们发现EZH2 抑制剂可以将CD4和CD8细胞重新招募到这些淋巴瘤中，我们认为这可能是主要的 FDA现在批准的这种治疗FLS的抗肿瘤机制。此外，我们已经证明了EZH2 抑制剂降低原代人EZH2突变淋巴瘤细胞的凋亡阈值并具有高度的协同作用 在活体内使用BH3模拟物，并正在进行一项联合他赛司他和万诺克拉克斯治疗FL的临床试验 和DLBCL患者。基于这些考虑和其他初步数据，我们假设EZH2 突变的FL依赖于从FDCs接收的信号，尤其是BAFF受体。我们建议 以FDC-FL B细胞免疫突触为靶点的治疗将对FLS造成致命打击，特别是当 与EZH2抑制剂联合用于恢复T细胞抗淋巴瘤免疫和BH3类似物，如万托克拉克斯。 我们希望这些治疗方法能够防止FL的进展和转化。我们这项提案的目标是 确定EZH2突变的FL B细胞是否依赖FDCs生存，EZH2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，并利用这一信息来测试新的结合 预防EZH2突变FLS进展和向侵袭性转化的治疗方法 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.