Developing newly combined therapeutic strategies for mature B cell lymphoma

虽然PD-1阻断对复发或难治性经典霍奇金淋巴瘤(CHL)和部分弥漫性大B细胞淋巴瘤(DLBCL)患者有效，但大多数B细胞淋巴瘤患者对这种抗PD-1免疫治疗没有反应。因此，有必要开发新的治疗策略来提高对免疫治疗的反应。然而，如何提高肿瘤的免疫原性以改善抗肿瘤免疫反应仍然知之甚少。在这方面，组蛋白脱乙酰酶(HDAC)抑制剂可以作为一种有吸引力的手段来实现这些目标，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，到目前为止，大多数HDAC抑制剂(HDACi)作为单一药物在治疗癌症方面并不是非常有效；这 这可能是因为不同的HDACi可以在癌症或正常细胞中引起高度不同的生物效应。此外，尽管HDACi对肿瘤细胞的细胞毒作用已被广泛研究，但对于HDACi如何影响免疫细胞以及HDACi在抗肿瘤免疫中的确切作用仍知之甚少。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不清楚。在这一应用中，我们建议阐明新开发的HDACi使B细胞淋巴瘤对PD-1治疗敏感的机制，并寻找预测HDACi和抗PD1抗体联合治疗效果的生物标志物。因此，我们建议的研究可能会通过开发新的治疗策略来针对由于免疫原性降低而对PD-1阻断产生抗性的癌症，从而使这一领域向前迈进一步。 最近，我们通过对激活的B细胞中DNA修复基因Xrcc4和Trp53的谱系特异性缺失，建立了一种独特的G1XP淋巴瘤小鼠模型。我们的初步数据显示，G1XP淋巴瘤类似于人类B细胞淋巴瘤的特征，并为测试针对免疫原性降低的淋巴瘤的新疗法提供了一个独特的实验平台。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、人源化B细胞淋巴瘤小鼠模型以及我们新开发的HDACi来验证我们的假设。

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.