The role of glioblastoma derived activated leukocyte cell adhesion molecule in peripheral monocyte PD-L1 induction and immunosuppression

 描述（由申请方提供）：多形性胶质母细胞瘤（GBM）是最常见的恶性中枢神经系统肿瘤，是一种致死性疾病。免疫疗法作为GBM的治疗方法，由于其产生持久、高度特异性抗肿瘤反应的潜力而引起了越来越多的关注。然而，迄今为止的临床疗效一直是温和的，部分原因是肿瘤诱导的免疫抑制。有效的免疫疗法依赖于攻击患者肿瘤的肿瘤特异性细胞毒性T淋巴细胞（CTL）的诱导。然而，CTL抗肿瘤活性可通过与GBM细胞、肿瘤相关巨噬细胞（TAM）和循环单核细胞表面上存在的程序性死亡配体1（PD-L1）相互作用而降低。因此，GBM患者在肿瘤微环境中局部经历免疫抑制，并且在外周循环中全身性经历免疫抑制。拟议工作的长期目标是通过鉴定，表征和调节GBM衍生的可溶性因子（GDSF）来改善GBM免疫治疗，这些因子有助于免疫抑制，特别是通过诱导骨髓细胞群中的PD-L1表达。初步证据表明：（1）外周单核细胞PD-L1表达升高预测免疫治疗GBM患者的结局更差，（2）一种GDSF（活化白细胞粘附分子（ALCAM））促进单核细胞中的PD-L1表达，（3）肿瘤诱导单核细胞中PD-L1的患者血浆中存在可溶性ALCAM（sALCAM）增加。鉴于这些关系，假设ALCAM的GBM表达在局部和全身诱导PD-L1中起作用。此外，假设抑制ALCAM本身和/或ALCAM诱导的刺激PD-L1表达的信号传导途径可通过降低骨髓细胞中的PD-L1表达来减少免疫抑制。在该提案的第一个目标中，我们将研究GBM患者ALCAM水平与循环单核细胞以及TAM中PD-L1表达之间的关系。此外，我们将探讨这些变量如何影响患者的生存和功能性免疫抑制。第二个目标将集中在确定参与ALCAM诱导的单核细胞PD-L1诱导的关键信号通路。通过这些分析，将有可能确定信号传导介质，可以有针对性地减少GBM诱导的单核细胞介导的免疫抑制。提出的第三个目标将评估ALCAM在鼠GBM模型中对抗肿瘤免疫应答、肿瘤生长和总存活率的作用。通过调节肿瘤细胞ALCAM的表达，我们希望为靶向ALCAM以减少免疫抑制和促进生存的益处提供临床前证据。通过这些实验，我们希望了解驱动免疫抑制的机制，这反过来又可以促进新策略的开发，以提高免疫抑制方法治疗GBM的疗效。

 DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM), the most common malignant central nervous system neoplasm, is a uniformly fatal disease. Immunotherapy as a treatment for GBM has garnered increasing interest due to its potential to generate a long-lasting, highly specific anti-tumor response. However, clinical efficacy to date has been modest, in part due to tumor-induced immunosuppression. Effective immunotherapy relies on induction of tumor-specific cytotoxic T lymphocytes (CTLs) that attack the patient's tumor. However, CTL anti-tumor activity can be reduced through interactions with programmed death ligand 1 (PD-L1) present on the surface of GBM cells, tumor associated macrophages (TAMs), and circulating monocytes. As a consequence, GBM patients experience immunosuppression locally in the tumor microenvironment, and systemically in the peripheral circulation. The long-term goal of the proposed work is to improve GBM immunotherapy through the identification, characterization, and modulation of GBM derived soluble factors (GDSFs) that contribute to immunosuppression, especially through induction of PD-L1 expression in the myeloid cell population. Preliminary evidence indicates that (1) elevated peripheral monocyte PD-L1 expression predicts worse outcomes in GBM patients treated with immunotherapy, that (2) one GDSF, activated leukocyte cell adhesion molecule (ALCAM), promotes PD-L1 expression in monocytes, and (3) increased soluble ALCAM (sALCAM) is present in the plasma of patients whose tumors induce PD-L1 in monocytes. Given these relationships, it is hypothesized that GBM expression of ALCAM plays a role in the induction of PD-L1, both locally and systemically. Furthermore, inhibition of ALCAM itself, and/or ALCAM-induced signaling pathways that stimulate PD-L1 expression, is hypothesized to reduce immunosuppression by decreasing PD-L1 expression in myeloid cells. In the first aim of the proposal, we will investigate the relationship between GBM patient ALCAM levels and PD-L1 expression in circulating monocytes as well as TAMs. Moreover, we will explore how these variables affect patient survival and functional immunosuppression. The second aim will focus on identifying key signaling pathways involved in ALCAM-induced monocyte PD-L1 induction. Through these analyses, it will be possible to identify signaling mediators that can be targeted to reduce GBM-induced, monocyte-mediated immunosuppression. The third proposed aim will evaluate the role of ALCAM on anti-tumor immune responses, tumor growth, and overall survival in a murine GBM model. Through modulation of tumor cell ALCAM expression, we hope to provide preclinical evidence for the benefit of targeting ALCAM to reduce immunosuppression and promote survival. Through these experiments, we hope to gain an understanding of the mechanisms driving immunosuppression, which, in turn, can promote the development of novel strategies to increase the efficacy of immunotherapeutic approaches for treating GBM.