Impact of Circulating Myeloid Cell Clusters on Anti-Tumor Immunity

循环骨髓细胞簇对抗肿瘤免疫的影响

• 批准号: 10543820
• 负责人: Scott I. Abrams
• 金额: $ 68.03万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543820
• 关键词: Active Sites; Address; Adhesives; Adoptive Cell Transfers; Adoptive Transfer; Advanced Malignant Neoplasm; Agonist; Antibodies; Antigens; Antineoplastic Agents; Apoptosis; Biological Markers; Blood; Blood flow; Breast Cancer Model; Breast Melanoma; CD3 Antigens; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Patient; Cell Communication; Cells; Cellular immunotherapy; Clinical; Clinical Trials; Cluster Analysis; Coculture Techniques; Complex; Cytotoxic T-Lymphocytes; Data; Destinations; Disseminated Malignant Neoplasm; Effector Cell; Equilibrium; Exclusion; Foundations; Genetic; Home; Homing; Human; ICAM2 gene; Immune; Immune checkpoint inhibitor; Immunity; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Integrins; Intercellular adhesion molecule 1; L-Selectin; Laboratories; Leukocytes; Ligands; Liver X Receptor; Lymphocyte; Lymphocyte Homing Receptors; Malignant Neoplasms; Mammary Neoplasms; Mediating; Memory; Metastatic breast cancer; Modeling; Mus; Myeloid Cell Suppression; Myeloid Cells; Myeloid-derived suppressor cells; Natural Immunity; Natural Killer Cells; Outcome; Patient Selection; Patients; Population; Pre-Clinical Model; Publishing; Regimen; Research; Residual state; Resistance; Site; Solid; Solid Neoplasm; Spleen; Splenectomy; Structure; Suppressor-Effector T-Lymphocytes; System; T cell response; T cell therapy; T memory cell; T-Lymphocyte; Testing; Therapeutic; Tissues; Travel; Treatment Efficacy; Tumor Immunity; Work; adaptive immunity; anti-cancer; blood-based biomarker; cancer immunotherapy; cancer therapy; checkpoint inhibition; chemokine; clinically relevant; cytotoxic CD8 T cells; defined contribution; fitness; genetic approach; human cancer mouse model; improved; in vivo; insight; interest; lymph nodes; lymphoid organ; melanoma; microscopic imaging; mouse model; new therapeutic target; novel; patient response; preconditioning; predicting response; predictive signature; prevent; prognostic indicator; prognostication; programs; receptor; recruit; resistance mechanism; response; stem cells; therapy resistant; trafficking; tumor; tumor microenvironment

Durable outcomes in subsets of solid cancer patients treated with immune checkpoint inhibitors (ICI) or adoptive cell transfer (ACT) immunotherapy has driven interest in gaining a better understanding of resistance mechanisms that could identify novel druggable targets. Myeloid-derived suppressor cells (MDSC) have emerged as one such barrier based on their ability to inhibit innate and adaptive immunity. While elevated blood MDSC are recognized as a poor prognostic indicator in cancer patients, it is widely thought that the main effector site for MDSC is within the tumor microenvironment (TME). This is in line with the well-documented contact- dependent mechanisms involving short-lived intermediates that underlie known mechanisms of T cell suppression by MDSC. Our published and preliminary studies enlarge on this view, showing that MDSC also function outside the TME through an unprecedented mechanism of intravascular immune suppression. The proposed study builds on our discovery that circulating MDSC initiate contact-dependent cleavage of the L- selectin homing receptor on target T cells that substantially reduces antigen-driven expansion of cytotoxic T cells in lymph nodes. We further found that L-selectin loss coincides with the formation of stable MDSC clusters in the blood of murine tumor models and advanced cancer patients. We term these new structures circulating myeloid cell (CMC) clusters. These observations led us to hypothesize that CMC clusters are an unrecognized functional niche for systemic immune suppression in cancer. To test this hypothesis, we will first determine if blood-borne MDSC target not only naïve T cells, but more broadly attack stem cell memory and central memory T cells and natural killer cells that each require L-selectin for their antitumor activity. Secondly, we will determine if CMC clusters are the active site of L-selectin cleavage by using a multipronged genetic approach to examine L-selectin fate following disruption of MDSC-T cell conjugate formation in vivo. These mechanistic studies center on β2 integrins that are highly expressed by MDSC but are normally inactive on leukocytes in fast-flowing blood under non-pathological conditions. Thirdly, we will examine the translational relevance of CMC clusters during ICI or ACT therapy in a preclinical model in which blood is the primary effector site for MDSC due to their exclusion from the TME (by blocking chemokine-directed trafficking) and spleen (by splenectomy). We will deplete circulating MDSC in this model using antibodies or a clinically relevant liver-X-receptor agonist that induces MDSC-intrinsic apoptosis to establish if blood-borne MDSC contribute to therapeutic resistance. Complementary studies will test the hypothesis that combining the analysis of circulating MDSC with CMC clusters and/or T cell L-selectin will formulate an immunosuppressive signature that predicts response to first-line therapy in metastatic cancer patients. The proposed studies will provide new insights into an unprecedented function of circulating myeloid cells and could lead to the consideration of CMC clusters as a functional biomarker for prognostication or preselection of patients that would benefit from MDSC-depleting regimens during cancer immunotherapy.

用免疫检查点抑制剂（ICI）或适应性治疗的固体癌症患者子集的持久结果 细胞转移（ACT）免疫疗法引起了人们对获得抗药性更好理解的兴趣 可以识别可识别可吸毒目标的机制。髓样衍生的抑制细胞（MDSC）具有 基于它们抑制先天和适应性免疫学的能力，成为这样的障碍。同时血液升高 MDSC被认为是癌症患者的预后指标差，人们普遍认为主要效应子 MDSC的位置在肿瘤微环境（TME）内。这与有据可查的联系人一致 - 依赖机制涉及的短寿命中间体是T细胞的已知机制的基础 MDSC抑制。我们出版的和初步的研究扩大了这一观点，表明MDSC也 通过血管内免疫抑制的前所未有的机制在TME之外的功能。这 拟议的研究以我们的发现为基础，即循环MDSC启动L-的接触依赖性裂解 在靶T细胞上选择素归巢受体，该受体大大降低了细胞毒性T细胞的抗原驱动的膨胀 在淋巴结中。我们进一步发现，L-选择素损失与稳定的MDSC簇形成一致 鼠肿瘤模型和晚期癌症患者的血液。我们称这些新结构流传于髓样 单元格（CMC）簇。这些观察结果导致我们假设CMC簇是一个未被认可的功能 癌症全身免疫抑制的利基市场。为了检验这一假设，我们将首先确定是否是血液传播 MDSC不仅靶向幼稚的T细胞，而且更广泛地攻击干细胞记忆和中央记忆T细胞，以及 每个需要L-选择素才能抗肿瘤活性的天然杀伤细胞。其次，我们将确定CMC是否 簇是L-选择素裂解的活性位点，使用多收益的遗传方法检查L-选择素 MDSC-T细胞结合形成在体内的破坏后的命运。这些机械研究以β2为中心 由MDSC高度表达但通常对快速流血的白细胞不活跃的整合素 非病理条件。第三，我们将研究ICI或ICI或 在临床前模型中的ACT疗法，由于其排除，血液是MDSC的主要效应部位 从TME（通过阻止趋化因子指导的运输）和脾脏（通过脾切除术）。我们将依靠 使用抗体或临床相关的肝脏-X受体激动剂在此模型中循环MDSC MDSC内膜细胞凋亡是确定血液传播MDSC是否有助于治疗性抗性。补充 研究将检验以下假设，即将循环MDSC与CMC簇和/或T细胞结合在一起 L-选择素将制定一种免疫抑制签名，该特征可以预测转移性一线治疗的反应 癌症患者。拟议的研究将为循环的前所未有的功能提供新的见解 髓样细胞，可能导致CMC簇作为编程的功能生物标志物 或在癌症免疫疗法期间将受益于MDSC耗竭方案的患者的预览。