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.

使用免疫检查点抑制剂（ICI）或过继治疗的实体癌患者亚群的持久结果 细胞转移（ACT）免疫疗法引发了人们对更好地了解耐药性的兴趣 可以识别新的可药物靶标的机制。 基于它们在升高血液的同时抑制先天性和适应性免疫的能力而成为这样的屏障之一。 MDSC被认为是癌症患者预后不良的指标，人们普遍认为其主要效应因子 MDSC 的位点位于肿瘤微环境 (TME) 内，这与有据可查的接触一致。 涉及 T 细胞已知机制基础的短寿命中间体的依赖性机制 我们发表的研究和初步研究进一步证实了这一观点，表明 MDSC 也抑制了这一观点。 通过前所未有的血管内免疫抑制机制在 TME 之外发挥作用。 拟议的研究建立在我们发现循环 MDSC 启动 L-接触依赖性裂解的基础上 靶 T 细胞上的选择素归巢受体可显着减少抗原驱动的细胞毒性 T 细胞的扩增 我们进一步发现 L-选择素的损失与稳定的 MDSC 簇的形成同时发生。 小鼠肿瘤模型和晚期癌症患者的血液我们将这些新结构称为循环骨髓。 这些观察结果使我们认为 CMC 簇是一种未被识别的功能。 为了检验这一假设，我们首先确定是否是血源性的。 MDSC 不仅针对幼稚 T 细胞，还更广泛地攻击干细胞记忆和中枢记忆 T 细胞， 每种自然杀伤细胞都需要 L-选择素来发挥其抗肿瘤活性 其次，我们将确定 CMC 是否有效。 通过使用多管齐下的遗传方法来检查 L-选择素，簇是 L-选择素裂解的活性位点 这些机制研究以 β2 为中心。 整合素在 MDSC 中高度表达，但通常在快速流动的血液中的白细胞上不活跃。 第三，我们将检查 ICI 或 ICI 期间 CMC 簇的翻译相关性。 临床前模型中的 ACT 治疗，其中血液由于排除而成为 MDSC 的主要效应部位 来自 TME（通过阻断趋化因子定向运输）和脾切除术（通过脾切除术）我们将耗尽。 在此模型中使用抗体或临床相关的肝脏 X 受体激动剂来诱导循环 MDSC MDSC 内在细胞凋亡以确定血源性 MDSC 是否会导致治疗耐药。 研究将检验以下假设：将循环 MDSC 分析与 CMC 簇和/或 T 细胞相结合 L-选择素将形成免疫抑制特征，预测转移性一线治疗的反应 拟议的研究将为癌症患者提供前所未有的循环功能的新见解。 骨髓细胞，并可能导致考虑将 CMC 簇作为预测的功能性生物标志物 或预选在癌症免疫治疗期间受益于 MDSC 消耗方案的患者。