Monocyte promotion of therapy resistance by immune and non-immune mechanisms

摘要 近年来，检查点抑制剂等免疫疗法已显示出令人兴奋的临床反应。 多年来，证明了宿主免疫系统在癌症中的重要作用。我们是第一个报告 以HLA-DR表达缺失为特征的免疫抑制单核细胞的新群体 (CD14+HLA-DRlow/neg)，在淋巴瘤、肾细胞癌、多形性胶质母细胞瘤等癌症类型中。 这些细胞在淋巴瘤肿瘤中呈PD-1阳性。我们已经刻画了这些的抑制功能 细胞对系统免疫的影响，并证明了这些细胞与PFS和OS减少的相关性。其他 研究人员已经报告了在其他癌症类型中的确凿发现。虽然该领域的许多人认为 这些细胞被称为单核细胞髓系衍生抑制细胞(MDSC)，基于它们的免疫功能，我们有 还发现了这些细胞直接促进化疗耐药的免疫非依赖性机制 淋巴瘤。因此，我们认为这些细胞比MDSC具有更广泛的功能范围，并具有 将它们定义为调节性单核细胞，Mreg。我们的中心假设是淋巴瘤肿瘤和mreg Croos Talk是导致抗淋巴瘤免疫抑制和 化疗耐药，从而降低存活率。在本R01提案中，我们将研究MREG 提高治疗抵抗力和确定潜在治疗策略的淋巴瘤串扰。这将是 通过三个具体目标来实现：1)确定MREG介导的淋巴瘤的机制 化疗耐药，特别关注Hsp27信号转导。动物模型将发展为 检测MREG淋巴瘤在化疗耐药中的相互作用，包括原发患者的肿瘤移植和 抑制HSP27的反义寡核苷酸apatorsen在固体药物临床试验中的检测 肿瘤。2)审查重新编程MREG以提高抗淋巴瘤免疫的策略，特别是 检测Hsp27和PD-1/PD-L1/L2对淋巴瘤MREG串扰和Toll样刺激的阻断作用 TLR7受体激动剂。此外，我们将研究一种新的脂质体包裹的药物输送系统，以 目标是Mreg。3)明确肿瘤内MREG的预后意义。完成目标1和目标2将 确定多种针对MREG淋巴瘤串扰的潜在治疗策略进行临床试验 发展。目标3的完成将有助于开发个性化治疗方法，其中 肿瘤内MREG水平高的患者将接受针对MREG淋巴瘤串扰的治疗。

Abstract Immunotherapies such as checkpoint inhibitors have demonstrated exciting clinical responses in the recent years, demonstrating the important role of host immune system in cancer. We were the first group to report a novel population of immunosuppressive monocytes, characterized by a loss of HLA-DR expression (CD14+HLA-DRlow/neg), in lymphoma, renal cell carcinoma, glioblastoma multiforme and other cancer types. These cells are PD-1 positive in lymphoma tumors. We have characterized the suppressive functions of these cells on systemic immunity and demonstrated correlation of these cells to decreased PFS and OS. Other researchers have reported corroborative findings in other cancer types. While many in the field have termed these cells as monocytic myeloid derived suppressor cells (MDSC) based on their immune functions, we have also identified immune independent mechanism by which these cells directly promote chemo-resistance in lymphoma. Therefore we believe that these cells have a broader spectrum of functions than MDSC and have defined them as regulatory monocytes, Mreg. Our central hypothesis is that lymphoma tumor and Mreg croos talk is a key mechanism that leads to suppression of anti-lymphoma immunity and chemotherapy resistance, thereby, reducing survival. In this R01 proposal, we will examine Mreg lymphoma crosstalk that promotes treatment resistance and identify potential therapeutic strategies. This will be achieved through three specific aims: 1) Identify the mechanisms of Mreg mediated lymphoma resistance to chemotherapy, specifically focusing on Hsp27 signaling. Animal model will be developed to examine Mreg lymphoma interaction in chemo-resistance, including primary patient tumor xenografts and testing of Apatorsen, an anti-sense oligonucleotide that inhibits Hsp27 in clinical trial development for solid tumors. 2) Examine strategies to reprogram Mreg to improve anti-lymphoma immunity, specifically testing blockade of Hsp27 and PD-1/PD-L1/L2 in lymphoma Mreg crosstalk and stimulation with toll-like receptor-7 (TLR7) agonist. In addition we will examine a novel liposome-packaged drug delivery system to target Mreg. 3) Identify the prognostic significance of intra-tumor Mreg. Completion of Aims 1 and 2 will identify more than one potential treatment strategies targeting Mreg lymphoma crosstalk for clinical trial development. Completion of Aim 3 will assist the development of a personalized therapy approach where patients with high levels intra-tumor Mreg will receive therapy targeting Mreg lymphoma crosstalk.