Tumor cell -TAM Paracrine Signaling in Breast Cancer

摘要 免疫检查点抑制剂被FDA批准用于转移性三阴性乳腺癌（TNBC）， 对于肿瘤浸润淋巴细胞（TIL）水平高的患者，这一点很好，但对于大多数BC患者， 代理人是无效的。需要继续研究以阐明肿瘤细胞和肿瘤细胞之间的相互作用。 原发性TME内不同的免疫细胞群，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（TAM）代表BC TME中最丰富的免疫组分之一， 对疾病有着强大而独特的影响。高水平的TAM浸润与不良预后相关 在BC。TAM在广泛的促肿瘤发生、促转移活性（包括肿瘤转移）中起关键作用。 血管生成、细胞外基质（ECM）重塑、免疫抑制和化学抗性。如何 克服TAM浸润和功能，以激活有效的抗肿瘤发生和抗转移反应 代表了业务连续性领域的知识差距。TAM最接近于M2极化型巨噬细胞 并在类别之间显示出一些重叠的功能。TAM是一种高度异质的可塑性细胞 具有促肿瘤功能的人群，通过M2与M1的总体丰度测量 标记。TAM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。尽管M2样极化被认为是促肿瘤发生的，但M1样极化被认为是促肿瘤发生的。 类极化与炎症、抗肿瘤作用和改善的预后有关。肿瘤细胞 产生旁分泌信号，募集和调节TAM功能。反过来，TAM会产生信号， 肿瘤细胞的转移潜力。鉴于TAM明确的促肿瘤和转移作用，似乎很明显， 确定消除促肿瘤发生M2样应答和促进抗肿瘤发生M1样应答的方法 在临床上是有利的。然而，有效的战略仍然难以捉摸。我们的建议引入了一个 一种新的靶向激酶的策略，称为HUNK，它有可能比 直接瞄准TAM。靶向HUNK将产生多方面的影响，不仅可以阻止促肿瘤/转移 肿瘤内在信号传导，而且从根本上改变肿瘤细胞之间的“前馈”旁分泌回路 和TAM。

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.