Tumor cell -TAM Paracrine Signaling in Breast Cancer

乳腺癌中的肿瘤细胞 -TAM 旁分泌信号传导

• 批准号: 10583793
• 负责人: Elizabeth S. Yeh
• 金额: $ 45.64万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-13 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583793
• 关键词: 4T1; Affect; Agonist; Antineoplastic Agents; Attenuated; Back; Breast Cancer Model; Breast Cancer cell line; Categories; Cells; Chemoresistance; Clinical; Data; Diagnosis; Disease; Down-Regulation; Endowment; Epidermal Growth Factor Receptor; Exhibits; Extracellular Matrix; FDA approved; Flow Cytometry; Genetic Transcription; Goals; Grant; Human; Immune; Immune checkpoint inhibitor; Immunohistochemistry; Immunosuppression; Impairment; Individual; Infiltration; Inflammatory; Interleukin 4 Receptor; Interleukin 6 Receptor; Interleukin-4; Invaded; Knowledge; Lymphocytic Infiltrate; Macrophage; Macrophage Activation; Mammary Neoplasms; Measures; Mediating; Methods; Modeling; Neoplasm Metastasis; Paracrine Communication; Patients; Phenotype; Phosphorylation; Phosphotransferases; Play; Population; Primary Neoplasm; Production; Prognosis; Receptor Signaling; Recovery; Regulation; Research; Role; Sampling; Shapes; Signal Pathway; Signal Transduction; Stat3 Signaling Pathway; Testing; Time; Tumor Angiogenesis; Tumor Biology; Tumor Promotion; Tumor-Infiltrating Lymphocytes; Tumor-associated macrophages; Up-Regulation; Work; antitumor effect; cell type; improved; in vivo; in vivo Model; knock-down; loss of function; malignant breast neoplasm; mammary; mouse model; neoplastic cell; paracrine; recruit; response; single-cell RNA sequencing; small hairpin RNA; therapeutic evaluation; transcription factor; triple-negative invasive breast carcinoma; tumor; tumor microenvironment; tumorigenic

ABSTRACT Immune checkpoint inhibitors are FDA approved for metastatic triple negative breast cancer (TNBC) and work well for patients with high levels of tumor infiltrating lymphocytes (TIL), but for the majority of BC patients, these agents are ineffective. Continued research is needed to elucidate the interplay between tumor cells and the diverse immune cell populations within the primary TME, and how this interaction shapes tumor biology. Tumor- associated macrophages (TAM) represent one of the most abundant immune components in BC TME and exhibit a robust and unique influence on the disease. High levels of TAM infiltration are associated with poor prognosis in BC. TAMs play a critical role in a wide range of pro-tumorigenic, pro-metastatic activities including tumor angiogenesis, extracellular matrix (ECM) remodeling, immunosuppression, and chemoresistance. How to surmount TAM infiltration and function in order to activate a potent anti-tumorigenic and anti-metastatic response represents a gap in knowledge for the BC field. TAMs most closely resemble M2-polarized type macrophages and exhibit some overlapping functions between the categories. TAMs are a highly heterogeneic, plastic cell population endowed with tumor-promoting functionality measured by the overall abundance of M2 vs M1 markers. TAM polarization and immunosuppressive capacities are dependent upon where these cells are located and what signals are received within the TME. Whereas M2-like polarization is considered pro-tumorigenic, M1- like polarization is associated with inflammatory, anti-tumor effects and improved prognosis. Tumor cells generate paracrine signals that recruit and regulate TAM function. In turn, TAMs produce signals that affect the metastatic potential of tumor cells. Given the clear pro-tumor and metastatic roles of TAMs, it seems evident that identifying ways to abrogate pro-tumorigenic M2-like responses and promote anti-tumorigenic M1-like responses in BC will be clinically advantageous. However, effective strategies remain elusive. Our proposal introduces a new strategy to target a kinase called HUNK that has the potential to be more advantageous than strategies that directly target TAMs. Targeting HUNK will have a multifaceted effect by not only halting pro-tumor/metastatic tumor intrinsic signaling but also fundamentally changing the “feed forward” paracrine loop between tumor cells and TAMs.

摘要 FDA批准免疫检查点抑制剂用于转移性三阴性乳腺癌(TNBC)和Work 对于肿瘤浸润性淋巴细胞(TIL)水平高的患者很好，但对于大多数BC患者来说，这些 特工是无效的。需要继续研究来阐明肿瘤细胞和肿瘤细胞之间的相互作用。 初级TME内的不同免疫细胞群，以及这种相互作用如何塑造肿瘤生物学。肿瘤- 相关巨噬细胞()是BC TME中含量最丰富的免疫成分之一，并展示了 对疾病有强大而独特的影响。浸润率高与预后不良有关 在公元前。TAMs在包括肿瘤在内的广泛的促肿瘤和促转移活动中发挥关键作用 血管生成、细胞外基质(ECM)重塑、免疫抑制和化疗耐药。如何 超越的渗透和作用，以激活强大的抗肿瘤和抗转移反应 表示BC领域的知识差距。TAMs与M2极化的巨噬细胞最为相似 并在类别之间表现出一些重叠的功能。TAMs是一种高度异质性的塑料细胞 被赋予肿瘤促进功能的人群，通过M2与M1的总体丰度来衡量 记号笔。极化和免疫抑制能力取决于这些细胞的位置 以及在TME内接收到什么信号。而类M2极化被认为是促肿瘤的，而M1- LIKE极化与炎症、抗肿瘤作用和改善预后有关。肿瘤细胞 产生旁分泌信号，招募和调节的功能。反过来，TAM产生的信号会影响 肿瘤细胞的转移潜能。考虑到TAMS明显的促肿瘤和转移作用，似乎很明显 确定消除促肿瘤M2样反应和促进抗肿瘤M1样反应的方法 在不列颠哥伦比亚省将是临床有利的。然而，有效的战略仍然难以捉摸。我们的提案引入了一个 靶向一种名为BUNK的激酶的新策略，它有可能比那些 直接瞄准TAMS。靶向大块头将具有多方面的效果，不仅可以阻止亲肿瘤/转移 肿瘤内在信号转导也从根本上改变了肿瘤细胞间的“前馈”旁分泌环路 还有塔姆斯。