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/文摘