Developing newly combined therapeutic strategies for mature B cell lymphoma

虽然PD-1阻断在复发性或难治性经典霍奇金淋巴瘤（cHL）和弥漫性大B细胞淋巴瘤（DLBCL）患者的亚组中有效，但大多数B细胞淋巴瘤患者对这种抗PD-1免疫疗法无应答。因此，有必要开发新的治疗策略以增强对免疫治疗的反应。然而，如何增强肿瘤免疫原性以改善抗肿瘤免疫应答仍然知之甚少。在这方面，组蛋白脱乙酰酶（HDAC）抑制剂可以作为实现这些目标的有吸引力的手段，例如，通过上调癌细胞系中的主要组织相容性复合体（MHC）和/或调节免疫细胞的功能。然而，迄今为止测试的大多数HDAC抑制剂（HDACi）作为单一药剂在治疗癌症方面不是非常有效;这可能是因为HDACi抑制剂的活性。 这可能是由于不同的HDACi可以在癌症或正常细胞中引起高度可变的生物学效应。此外，尽管HDACi对肿瘤细胞的细胞毒性作用已被广泛研究，但仍不清楚HDACi如何影响免疫细胞以及HDACi在抗肿瘤免疫中的确切作用。重要的是，如何对癌症进行分层以识别HDACi敏感亚型在很大程度上仍然是未知的。在本申请中，我们提出阐明新开发的HDACi使B细胞淋巴瘤对PD-1治疗敏感的机制，并鉴定预测HDACi和抗PD 1抗体联合治疗疗效的生物标志物。因此，我们提出的研究可以通过开发新的治疗策略来靶向由于免疫原性降低而对PD-1阻断具有抗性的癌症，从而将该领域向前推进一步。 我们最近通过在活化的B细胞中特异性删除Xrcc 4（DNA修复基因）和Trp 53，建立了一种独特的G1 XP淋巴瘤小鼠模型。我们的初步数据表明，G1 XP淋巴瘤类似于人类B细胞淋巴瘤的特征，并提供了一个独特的实验平台，用于测试新的治疗方法，目标淋巴瘤的免疫原性降低。我们的目标是开发新的组合策略来治疗侵袭性B细胞淋巴瘤。为此，我们将使用小鼠B细胞淋巴瘤模型、B细胞淋巴瘤的人源化小鼠模型和我们新开发的HDACi来检验我们的假设。

While PD-1 blockade is effective in relapsed or refractory classical Hodgkin lymphoma (cHL) and in a subset of diffuse large B cell lymphomas (DLBCL) patients, a majority of B cell lymphoma patients do not respond to such anti-PD-1 immunotherapy. Hence, it is necessary to develop new therapeutic strategies to enhance responses to mmunotherapy. However, it remains poorly understood how to enhance tumor immunogenicity to improve anti-tumor immune responses. In this regard, histone deacetylase (HDAC) inhibitors may serve as an attractive means to achieve such goals, e.g., by upregulating major histocompatibility complex (MHC) in cancer cell lines and/or modulating immune cells' functions. Nevertheless, most HDAC inhibitors (HDACi) tested so far are not very effective in treating cancers as a single agent; this may be due to the fact that different HDACi can cause highly variable biological effects in cancer or normal cells. Furthermore, although the cytotoxic effects of HDACi on tumor cells have been studied extensively, it remains poorly understood how HDACi affect immune cells and what precise role HDACi have in anti-tumor immunity. Importantly, it remains largely unknown how to stratify cancers to identify the HDACi sensitive subtypes. In this application, we propose to elucidate the mechanisms by which a newly developed HDACi sensitizes B cell lymphomas to PD-1 therapy, and identify biomarkers that predict the efficacy of combined treatment of HDACi and anti-PD1 antibody. Hence, our proposed studies may advance the field one step forward by developing novel therapeutic strategies to target cancers resistant to PD-1 blockade due to reduced immunogenicity. We recently established a unique mouse model of G1XP lymphomas by lineage-specific deletion of Xrcc4, a DNA repair gene, and Trp53 in activated B cells. Our preliminary data show that G1XP lymphomas resemble the features of human B cell lymphomas and provide a unique experimental platform for testing new therapies that target lymphomas with reduced immunogenicity. Our objective here is to develop novel combinatorial strategies to treat aggressive B cell lymphomas. To do so, we will test our hypothesis using mouse B cell lymphoma models, humanized mouse models for B cell lymphoma, and our newly developed HDACi.