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

摘要 免疫疗法，如检查点抑制剂，在最近的临床试验中已经证明了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 一种新的免疫抑制性单核细胞群，其特征为HLA-DR表达缺失 (CD14+ HLA-DR低/阴性），在淋巴瘤、肾细胞癌、多形性胶质母细胞瘤和其他癌症类型中。 这些细胞在淋巴瘤肿瘤中是PD-1阳性的。我们已经描述了这些抑制功能的特征， 细胞对全身免疫的影响，并证明这些细胞与PFS和OS降低相关。 研究人员报告了其他癌症类型的确证性发现。虽然许多业内人士称之为 这些细胞作为单核细胞髓源性抑制细胞（MDSC）基于其免疫功能，我们有 还确定了这些细胞直接促进化疗耐药性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， 将其定义为调节性单核细胞，Mreg.我们的中心假设是淋巴瘤和Mreg croos talk是导致抗淋巴瘤免疫抑制的关键机制， 化疗耐药性，从而降低存活率。在此R 01提案中，我们将研究Mreg 淋巴瘤串扰，促进治疗耐药性，并确定潜在的治疗策略。这将 通过三个具体目标实现：1）确定Mreg介导的淋巴瘤的机制 对化疗的抗性，特别关注Hsp 27信号传导。将开发动物模型， 检查Mreg淋巴瘤在化疗耐药性中的相互作用，包括原发性患者肿瘤异种移植物， Apatorsen是一种反义寡核苷酸，可抑制Hsp 27在固体药物临床试验开发中的作用。 肿瘤的2)检查重新编程Mreg以提高抗淋巴瘤免疫力的策略，特别是 淋巴瘤中Hsp 27和PD-1/PD-L1/L2的测试阻断Mreg串扰和Toll样刺激 受体-7（TLR 7）激动剂。此外，我们将研究一种新型的脂质体包装的药物输送系统， 目标Mreg。3)确定肿瘤内Mreg的预后意义。目标1和2的完成将 确定一种以上针对Mreg淋巴瘤串扰的潜在治疗策略用于临床试验 发展目标3的完成将有助于开发个性化治疗方法， 肿瘤内Mreg水平较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.