Targeting macrophages to sensitize myeloma to immune checkpoint blockade

项目摘要 免疫检查点阻断已成为一种通过恢复T细胞效应来治疗癌症的有前途的方法 功能和破坏允许肿瘤的微环境。临床疗效显著，疗效持久， PD-1检查点阻断的低毒性已在各种恶性肿瘤中观察到，包括 血液病癌症。然而，在尼伏卢单抗(抗PD-1抗体；BMS-936558)的1期研究中，没有一个 27例多发性骨髓瘤(MM)患者部分或完全缓解，而客观 约40%的滤泡性淋巴瘤或弥漫性大B细胞淋巴瘤患者有反应。 正如我们和其他人已经证明的那样，MM细胞表达高水平的PD-L1，骨髓(BM)浸润性T细胞 细胞大多为PD-1阳性，更重要的是，MM细胞携带的体细胞突变数量与AS相似 B细胞淋巴瘤，对多发性骨髓瘤PD-1抗体治疗无反应不能用缺乏 MM细胞或免疫细胞表达肿瘤浸润性T细胞或PD-L1或新抗原。我们推测 仅有PD-1/PD-L1检查站封锁不足以打破MM中允许的微环境 因为骨髓浸润性免疫抑制细胞，如肿瘤相关的MΦS，髓系来源的抑制因子 细胞(MDSCs)和/或调节性T细胞(Tregs)仍然可以抑制MM特异性效应T细胞的功能 被检查站封锁恢复了。事实上，我们的初步研究表明，与人类MM类似，PD-1 单抗对已建立的小鼠多发性骨髓瘤无明显治疗作用。然而，令我们惊讶的是， 体内耗尽MΦS，而不是MDSCs或Treg细胞，导致PD-1后显著的抗MM效应 检查站封锁。这个应用将验证我们的假设，即MΦS，作为BM的主要渗透者之一 细胞类型，在抑制肿瘤微环境中的T细胞免疫和靶向这些细胞方面是至关重要的 将显著提高检查点封锁对MM患者的治疗效果。 确定M-ΦS在PD-1关卡阻断治疗耐药中的作用及机制 目的2将阐明MΦ介导的免疫抑制的机制，目的3将确定 联合MΦ靶向和PD-1抗体治疗人类多发性骨髓瘤的翻译潜能 这些目的将为临床靶向BM浸润性MΦS使MM患者敏感提供理据和工具 到PD-1检查点抑制剂。拟议的研究还将使我们更好地了解 抵抗PD-1检查站封锁的主要机制，可能为第一次 靶向治疗多发性骨髓瘤和其他血液系统恶性肿瘤的实质性进展 M-Φ、S和PD-1抑制作用。

Project Summary Immune checkpoint blockade has emerged as a promising approach to treat cancer by restoring T cell effector function and breaking a tumor-permissive microenvironment. Remarkable clinical efficacy, durable response, and low toxicity of PD-1 checkpoint blockade have been observed in various malignancies including hematological cancers. However, in a phase 1 study of nivolumab (anti-PD-1 antibody; BMS-936558), none of 27 patients with multiple myeloma (MM) experienced a partial or complete response, whereas objective responses were observed in about 40% of patients with follicular lymphoma or diffuse large B cell lymphoma. As we and others have shown that MM cells express high levels of PD-L1, that bone marrow (BM)-infiltrating T cells are largely PD-1 positive, and more importantly MM cells carry somatic mutations in amounts similar to as B-cell lymphomas, the absence of response to PD-1 antibody therapy for MM cannot be explained by a lack of tumor-infiltrating T cells or PD-L1 or neoantigen expression by MM cells or immune cells. We speculated that PD-1/PD-L1 checkpoint blockade alone is insufficient to break the permissive microenvironment in MM because BM-infiltrating immunosuppressive cells, such as tumor-associated MΦs, myeloid-derived suppressor cells (MDSCs), and/or regulatory T cells (Tregs) could still inhibit the function of MM-specific effector T cells restored by the checkpoint blockade. Indeed, our preliminary studies showed that, similar to human MM, PD-1 mAbs had no significant therapeutic effect against established MM in murine models. However, to our surprise, in vivo depletion of MΦs, but not MDSCs or Tregs, resulted in significant anti-MM effects following PD-1 checkpoint blockade. This application will test our hypothesis is that MΦs, as one of the major BM-infiltrating cell types, are crucial in suppressing T-cell immunity in the tumor microenvironment, and targeting these cells will significantly improve the therapeutic efficacy of checkpoint blockade in patients with MM. Aim 1 will determine the role and mechanism of MΦs in the primary resistance to PD-1 checkpoint blockade therapy in MM. Aim 2 will elucidate the mechanisms of MΦ-mediated immune suppression, and Aim 3 will determine the translational potential of combining MΦ-targeting and PD-1 antibodies to treat human MM. Accomplishing these aims will provide the justification and tools to clinically target BM-infiltrating MΦs to sensitize MM patients to PD-1 checkpoint inhibitors. The proposed studies will also lead to a better understanding of the fundamental mechanisms underlying the primary resistance to PD-1 checkpoint blockade and could pave the way to the first substantial improvements in the treatment in MM and other hematological malignancies by way of targeting MΦs and PD-1 inhibition.