Diagnostic value of ^18F-FDG-PET to predict the tumour immune status defined by tumoural PD-L1 and CD8^+tumour-infiltrating lymphocytes in oral squamous cell carcinoma
^ 18F-FDG-PET 预测口腔鳞状细胞癌肿瘤 PD-L1 和 CD8 ^ + 肿瘤浸润淋巴细胞肿瘤免疫状态的诊断价值
- 作者列表："Togo, Maria","Yokobori, Takehiko","Shimizu, Kimihiro","Handa, Tadashi","Kaira, Kyoichi","Sano, Takaaki","Tsukagoshi, Mariko","Higuchi, Tetsuya","Yokoo, Satoshi","Shirabe, Ken","Oyama, Tetsunari
Background Lately, immune checkpoint proteins, such as programmed death 1 (PD-1) and its ligand-1 (PD-L1), have garnered attention as a new target in oral squamous cell carcinoma (OSCC). Reportedly, fluoro- d -glucose (FDG)-uptake alteration by anti-PD-1 antibody treatment depicts the response in patients with lung cancer. This study aims to elucidate the correlations between tumour immune status, clinicopathological factors, ^18F-FDG-uptake and cold tumour phenotypes as low PD-L1 expression/low CD8^+tumour-infiltrating lymphocytes (TILs) in OSCC. Methods We performed immunohistochemical analysis of PD-L1, hypoxia-inducible factor 1 A (HIF-1A), glucose transporter type 1 (GLUT1), CD8, E-cadherin and Ki-67 on 59 operable OSCC samples. We assessed the correlations between these factors and preoperative ^18F-FDG-uptake, clinicopathological characteristics and prognosis. Results Low expression of PD-L1 in OSCC correlated with cancer aggressiveness, poor prognosis, high ^18F-FDG-uptake with HIF-1A/GLUT1 and low E-cadherin expression and low CD8. Cold tumour phenotypes as low PD-L1 tumour cells and low stromal CD8 correlated with the poor prognosis, high ^18F-FDG-uptake and E-cadherin suppression. Furthermore, the high level of preoperative ^18F-FDG-uptake in OSCC was an independent predictor of the cold tumour immune status. Conclusions ^18F-FDG-uptake is an independent predictor of cold tumour in OSCC. ^18F-FDG-PET imaging could be a promising diagnostic tool to estimate tumour immune status.
背景: 最近，免疫检查点蛋白，如程序性死亡 1 (PD-1) 及其 ligand-1 (PD-L1)，作为一个新的靶点在口腔鳞状细胞癌 (OSCC) 中受到关注。据报道，通过 anti-PD-1 抗体治疗的氟-d-葡萄糖 (FDG) 摄取改变描述了肺癌患者的反应。本研究旨在探讨 OSCC 中肿瘤免疫状态、临床病理因素、 ^ 18f-fdg 摄取与 PD-L1 低表达/低 CD8 ^ + 肿瘤浸润淋巴细胞 (til) 的关系。方法对 59 例手术切除的 OSCC 标本进行 PD-L1 、缺氧诱导因子 1 a (HIF-1A) 、葡萄糖转运蛋白 1 (GLUT1) 、 CD8 、 E-cadherin 和 Ki-67 的免疫组化分析。我们评估了这些因素与术前 ^ 18f-fdg 摄取、临床病理特征和预后之间的相关性。结果 OSCC 中 PD-L1 低表达与肿瘤侵袭性、不良预后、高 ^ 18f-fdg 摄取 (HIF-1A/GLUT1) 、低 E-cadherin 表达和低 cd8 相关。低 PD-L1 肿瘤细胞和低间质 CD8 与预后不良、高 ^ 18f-fdg-摄取和 E-cadherin 抑制相关。此外，OSCC 术前 ^ 18f-fdg-摄取水平高是冷肿瘤免疫状态的独立预测因子。结论 ^ 18f-fdg 摄取是 OSCC 冷肿瘤的独立预测因子。^ 18F-FDG-PET 成像可能是估计肿瘤免疫状态的一种有前途的诊断工具。
METHODS::Macrophages (MΦ) play a critical role in tumor growth, immunosuppression and inhibition of adaptive immune responses in cancer. Hence, targeting signaling pathways in MΦs that promote tumor immunosuppression will provide therapeutic benefit. PI3Kγ has been recently established by our group and others as a novel immuno-oncology target. Herein, we report that a macrophage Syk-PI3K axis drives polarization of immunosuppressive MΦs which establish an immunosuppressive tumor microenvironment in in vivo syngeneic tumor models. Genetic or pharmacological inhibition of Syk and/or PI3Kγ in MΦs promotes a pro-inflammatory MΦphenotype, restores CD8+ T cell activity, destabilizes HIF under hypoxia, and stimulates an antitumor immune response. Assay for Transposase-accessible Chromatin using Sequencing (ATAC-seq) analyses on the bone marrow derived macrophages (BMDMs) show that inhibition of Syk kinase promotes activation and binding of NF-κB motif in SykMC-KO BMDMs, thus stimulating immunostimulatory transcriptional programming in MΦs to suppress tumor growth. Finally, we have developed in silico the "first in class" dual Syk/PI3K inhibitor, SRX3207, for the combinatorial inhibition of Syk and PI3K in one small molecule. This chemotype demonstrates efficacy in multiple tumor models and represents a novel combinatorial approach to activate antitumor immunity.
METHODS::Dysfunction of invariant natural killer T (iNKT) cells in tumor microenvironment hinders their anti-tumor efficacy, and the underlying mechanisms remain unclear. Here we report that iNKT cells increase lipid biosynthesis after activation, and that is promoted by PPARγ and PLZF synergically through enhancing transcription of Srebf1. Among those lipids, cholesterol is required for the optimal IFN-γ production from iNKT cells. Lactic acid in tumor microenvironment reduces expression of PPARγ in intratumoral iNKT cells and consequently diminishes their cholesterol synthesis and IFN-γ production. Importantly, PPARγ agonist pioglitazone, a thiazolidinedione drug for type 2 diabetes, successfully restores IFN-γ production in tumor-infiltrating iNKT cells from both human patients and mouse models. Combination of pioglitazone and alpha-galactosylceramide treatments significantly enhances iNKT cell-mediated anti-tumor immune responses and prolongs survival of tumor-bearing mice. Our studies provide a strategy to augment the anti-tumor efficacy of iNKT cell-based immunotherapies via promoting their lipid biosynthesis.
METHODS::Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed and selective cancer treatment that induces necrotic and immunogenic cell death and utilizes a monoclonal antibody conjugated to a photo-absorber dye, IR700DX, activated by NIR light. Although CD44 is surface cancer marker associated with drug resistance, anti-CD44-IR700 NIR-PIT results in inhibited cell growth and prolonged survival in multiple tumor types. Meanwhile, anti-CD25-IR700-targeted NIR-PIT has been reported to achieve selective and local depletion of FOXP3+CD25+CD4+ regulatory T cells (Tregs), which are primary immunosuppressive cells in the tumor microenvironment (TME), resulting in activation of local antitumor immunity. Combined NIR-PIT with CD44- and CD25-targeted agents has the potential to directly eliminate tumor cells and also amplify the immune response by removing FOXP3+CD25+CD4+ Tregs from the TME. We investigated the difference in therapeutic effects of CD44-targeted NIR-PIT alone, CD25-targeted NIR-PIT alone, and the combination of CD44- and CD25-targeted NIR-PIT in several syngeneic tumor models, including MC38-luc, LL/2, and MOC1. The combined NIR-PIT showed significant tumor growth inhibition and prolonged survival compared with CD44-targeted NIR-PIT alone in all tumor models and showed prolonged survival compared with CD25-targeted NIR-PIT alone in MC38-luc and LL/2 tumors. Combined CD44/CD25 NIR-PIT also resulted in some complete remissions, whereas this was not achieved with either type of NIR-PIT alone. Therefore, combined NIR-PIT simultaneously targeting cancer antigens and immunosuppressive cells in the TME may be more effective than either type of NIR-PIT alone and may have potential to induce prolonged immune responses in treated tumors.