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: 10322156
• 负责人: Scott I. Abrams
• 金额: $ 69.42万
• 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/10322156
• 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; Lead; 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; base; blood-based biomarker; cancer immunotherapy; cancer therapy; checkpoint inhibition; chemokine; clinically relevant; cytotoxic CD8 T cells; defined contribution; fitness; genetic approach; 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.

接受免疫检查点抑制剂(ICI)或过继治疗的实体癌症患者亚群的持久结果 细胞转移(ACT)免疫疗法引起了人们对更好地了解耐药性的兴趣 可以识别新的可用药靶点的机制。髓系来源的抑制细胞(MDSC)有 根据它们抑制先天免疫和获得性免疫的能力，出现了这样的障碍。当血液升高时 MDSC被认为是癌症患者预后不良的指标，被广泛认为是主要的影响因素 MDSC的部位在肿瘤微环境(TME)内。这与有充分记录的联系方式一致- 涉及短寿命中间体的依赖机制是T细胞已知机制的基础 由MDSC进行抑制。我们已发表的和初步的研究扩大了这一观点，表明MDSC也 通过一种前所未有的血管内免疫抑制机制在TME之外发挥作用。这个 拟议的研究建立在我们的发现基础上，循环中的MDSC启动了L的接触依赖性切割- 靶T细胞上的选择素归巢受体可显著减少抗原驱动的细胞毒性T细胞的增殖 在淋巴结里。我们进一步发现，L-选择素的丢失与稳定的MDSC团簇的形成是一致的。 小鼠肿瘤模型和晚期癌症患者的血液。我们称这些新结构为循环髓系 细胞(CMC)簇。这些观察结果使我们假设CMC星团是一种无法识别的功能 癌症全身性免疫抑制的利基。为了验证这一假设，我们将首先确定血液传播 MDSC不仅针对幼稚的T细胞，而且更广泛地攻击干细胞记忆和中央记忆T细胞 自然杀伤细胞，每个细胞都需要L-选择素来发挥抗肿瘤活性。其次，我们将确定CMC是否 用多管齐下的遗传学方法检测L-选择素的活性部位 体内MDSC-T细胞结合物形成中断后的命运。这些机理研究以β2为中心 在快速流动的血液中，MDSC高表达但通常在白细胞上不活跃的整合素 非病理状态。第三，我们将在ICI期间检查CMC集群的翻译相关性 临床前模型中的ACT治疗，在该模型中，由于MDSC的排斥，血液是MDSC的主要效应部位 来自TME(通过阻断趋化因子导向的运输)和脾(通过脾切除)。我们将耗尽 在这个模型中使用抗体或临床相关的肝X受体激动剂诱导循环MDSC MDSC的内源性凋亡以确定血源性MDSC是否与治疗耐药有关。互补性 研究将检验这样一种假设，即结合循环MDSC与CMC簇和/或T细胞的分析 L-选择素将制定一种免疫抑制签名，预测转移性肿瘤一线治疗的反应 癌症患者。拟议的研究将为了解循环这一前所未有的功能提供新的见解 并可能导致考虑将CMC簇作为预测的功能生物标记物 或预先选择在癌症免疫治疗期间将受益于MDSC耗尽方案的患者。