Targeting tumor-associated macrophages for triple-negative breast cancer treatment

靶向肿瘤相关巨噬细胞进行三阴性乳腺癌治疗

• 批准号: 10365772
• 负责人: Mingye Feng
• 金额: $ 53.82万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10365772
• 关键词: Antineoplastic Agents; B-Lymphocytes; Biological Assay; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Treatment; CD47 gene; Cell Surface Receptors; Cell surface; Cells; Chemoresistance; Chemotherapy-Oncologic Procedure; Clinical; Development; ERBB2 gene; Eating; Engraftment; Epidermal Growth Factor Receptor; Estrogen Receptors; Estrogens; Excision; FDA approved; Hematopoietic Neoplasms; Human; Immune; Immune Evasion; Immune system; Immunologic Surveillance; Immunotherapeutic agent; Immunotherapy; In Vitro; Infiltration; Journals; Light; Malignant - descriptor; Malignant Neoplasms; Mediating; Molecular; Mus; Natural Killer Cells; PD-L1 blockade; Pathway interactions; Pattern recognition receptor; Phagocytes; Phagocytosis; Pre-Clinical Model; Primary Neoplasm; Progesterone; Progesterone Receptors; Prognosis; Resistance; Resistance development; Role; Signal Pathway; Signal Transduction; Solid Neoplasm; Subgroup; T-Lymphocyte; Therapeutic; Tumor Escape; Tumor-associated macrophages; Up-Regulation; anti-PD-L1 antibodies; anti-cancer; base; cancer cell; cancer immunotherapy; cancer therapy; chemotherapeutic agent; cytotoxicity; effective therapy; efficacy evaluation; improved; in vivo; macrophage; malignant breast neoplasm; mouse model; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; pre-clinical; receptor; screening; small molecule; therapeutic target; therapeutically effective; triple-negative invasive breast carcinoma; tumor; tumor microenvironment

Project Summary/Abstract Triple-negative breast cancer (TNBC) is characterized by the lack of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2, all of which are important therapeutic targets. TNBC is the most difficult-to-treat subgroup of breast cancers and is resistant to many current cancer therapies. The present situation of poor prognosis with limited therapy options in TNBC emphasizes an urgent need for more effective therapeutics. The ability to escape from the surveillance by the immune system is regarded as one of the essential hallmarks of cancer cells. Recent exciting discoveries have identified many important signals and mechanisms mediating cancer cell immune evasion. Immunotherapies have been developed to target these signals, revolutionizing the treatment of a variety of human cancers. Tumor-associated macrophages (TAMs) represent the major components of the tumor microenvironment in TNBC. Recent studies demonstrate that the blockade of a “don’t eat me” signal CD47 leads to direct phagocytosis of living cancer cells by macrophages, and significantly inhibits the engraftment of various malignant hematopoietic and solid tumor cells in mice that lack T, B, and NK cells, indicating a critical role of macrophages in cancer immunosurveillance. Targeting TAMs in the tumor microenvironment represents a new class of promising cancer immunotherapy. While inducing anticancer functions of TAMs holds considerable promise for cancer treatment, there are several barriers that need to be overcome to achieve desired efficacy for treating TNBC. In preliminary studies, we found that TAMs can be reprogrammed by small molecule antineoplastic compounds to induce their phagocytic ability against TNBC cells. However, the underlying molecular mechanisms regulating the reprogramming of macrophages remains unclear. The overall objective of the proposed study is to understand the underlying mechanisms of macrophage-mediated immunosurveillance in TNBC and to develop strategies to effectively treat TNBC by exploiting tumoricidal roles of TAMs, with a combination of in vitro and in vivo preclinical TNBC models. In Aim1, we will assess the efficacy of reprogramming macrophages in TNBC treatment by using metastatic TNBC models and chemotherapy-resistant patient-derived xenograft models. In Aim2, we will study the molecular mechanisms by which macrophages are reprogrammed by dissecting the functions and roles of Pattern Recognition Receptor signaling pathways in macrophage reprogramming and characterizing TAM subgroups in TNBC tumors. In Aim3, we will determine the effects of targeting macrophage cell surface molecular machinery on activating TAMs for TNBC treatment. Successful completion of the proposed studies should shed light on the basic principles of cancer cell immune evasion and inspire the development of novel therapeutics for TNBC treatment.

项目总结/摘要 三阴性乳腺癌（TNBC）的特点是缺乏雌激素受体、孕激素受体 和人表皮生长因子受体2，它们都是重要的治疗靶点。TNBC是世界上 难治性乳腺癌亚组，对目前的许多癌症疗法具有耐药性。本 TNBC预后不良且治疗选择有限的情况强调了迫切需要更有效的 治疗学逃避免疫系统监视的能力被认为是免疫系统的一个重要特征。 癌细胞的基本特征最近令人兴奋的发现已经确定了许多重要的信号， 介导癌细胞免疫逃避的机制。免疫疗法已经开发出针对这些 信号，彻底改变了各种人类癌症的治疗。肿瘤相关巨噬细胞（TAM） 代表TNBC中肿瘤微环境的主要组分。最近的研究表明， 阻断“不要吃我”信号CD 47导致巨噬细胞直接吞噬活癌细胞， 并显著抑制小鼠中各种恶性造血细胞和实体瘤细胞的植入， 缺乏T、B和NK细胞，表明巨噬细胞在癌症免疫监视中的关键作用。靶向TAMs 代表了一类新的有前途的癌症免疫疗法。同时诱导 TAM的抗癌功能为癌症治疗带来了相当大的希望，但存在几个障碍， 需要克服这些困难以实现治疗TNBC的期望功效。在初步研究中，我们发现TAM 可以被小分子的抗肿瘤化合物重编程，以诱导它们的吞噬能力， TNBC细胞。然而，调节巨噬细胞重编程的潜在分子机制 仍不清楚这项研究的总体目标是了解 巨噬细胞介导的免疫监视，并制定有效治疗TNBC的策略， 利用TAM的杀肿瘤作用，结合体外和体内临床前TNBC模型。在目标1中， 我们将通过使用转移性TNBC模型评估重编程巨噬细胞在TNBC治疗中的功效 和化疗抗性患者来源的异种移植物模型。在Aim 2中，我们将研究 通过剖析模式识别受体的功能和作用， 在巨噬细胞重编程和表征TNBC肿瘤中的TAM亚组中的信号传导途径。在目标3中， 我们将确定靶向巨噬细胞表面分子机制对激活TAM的影响， TNBC治疗。成功完成拟议的研究应有助于阐明 癌细胞免疫逃避，并启发开发用于TNBC治疗的新疗法。