A New Immunological Prognostic Model Based on Immunohistochemistry for Extranodal Natural Killer/T-Cell Lymphoma Patients After Non-Anthracycline-Based Chemotherapy.
- 作者列表："Lam ST","Huang H","Fang X","Wang Z","Hong H","Ren Q","Tian Y","Lin S","Lin T
Purpose:Programmed death ligand 1 (PD-L1) has been proposed as an important prognostic factor in many types of cancer. However, the role of predicting the prognosis of PD-L1 in extranodal natural killer/T-cell lymphoma (ENKTL) was controversial. Combining other biomarkers might enhance its predictive power. This study aims to evaluate the prognostic value of PD-L1 in conjunction with tumor-infiltrating FoxP3+Tregs for ENKTL after non-anthracycline-based chemotherapy. Patients and Methods:A total of 81 patients with ENKTL were included in this study. Clinicopathological characteristics were collected, and prognostic significance of PD-L1 in neoplastic cells (nPD-L1) and tumor-infiltrating FoxP3+Tregs were evaluated. Results:Patients with nPD-L1-positive had significantly inferior overall survival (OS) and progression-free survival (PFS) compared with nPD-L1-negative (3-year OS, 37.2% vs 67.3%, p = 0.014; 3-year PFS, 31.0% vs 61.8%, p =0.010, respectively). Patients who had low FoxP3+Tregs had significantly inferior OS and PFS compared with high FoxP3+Tregs (3-year OS, 36.4% vs 63.0%, p = 0.004; 3-year PFS, 31.7% vs 56.3%, p = 0.020, respectively). The results of multivariate analysis showed that nPD-L1 positivity (HR 6.629, 95% CI 1.966-22.350, p=0.002) and low FoxP3+Tregs (HR 7.317, 95% CI 2.154-24.855, p=0.001) were independent predictors of inferior OS. Using these 2 variables, we constructed a new prognostic model that singled out 3 groups with different risk profiles: group 1, no adverse factors; group 2, 1 adverse factor; and group 3, 2 adverse factors. The 3-year OS rates of group 1, group 2, and group 3 were 93.3%, 46.6% and 20.8%, respectively (p<0.001), and the 3-year PFS rates were 86.7%, 40.8% and 15.0%, respectively (p=0.001). Conclusion:This study is the first to validate the prognostic value of nPD-L1 and tumor-infiltrating FoxP3+Tregs in ENKTL; the new immunological prognostic model might be used to stratify ENKTL patients in clinical trials for new therapeutic strategies.
目的: 程序性死亡配体 1 (PD-L1) 被认为是多种癌症的重要预后因子。然而，预测结外自然杀伤/T 细胞淋巴瘤 (ENKTL) PD-L1 预后的作用存在争议。结合其他生物标志物可能会增强其预测能力。本研究旨在评估 PD-L1 联合肿瘤浸润 FoxP3 + Tregs 对非蒽环类药物化疗后 ENKTL 的预后价值。 患者和方法: 本研究共纳入 81 例 ENKTL 患者。收集临床病理特征，评估肿瘤细胞 (PD-L1) 和肿瘤浸润 FoxP3 + Tregs 中 nPD-L1 的预后意义。 结果: nPD-L1-positive 患者总生存期 (OS) 和无进展生存期 (PFS) 明显低于 nPD-L1-negative (3 年 OS，37.2% vs 67.3%，p = 0.014); 3 年 PFS，分别为 31.0% vs 61.8%，p = 0.010)。与高 FoxP3 + Tregs 相比，低 FoxP3 + Tregs 患者的 OS 和 PFS 显著较差 (3 年 OS，36.4% vs 63.0%，p = 0.004; 3 年 PFS,分别为 31.7% vs 56.3%，p = 0.020)。多因素分析结果显示，nPD-L1 阳性 (HR 6.629，95% CI 1.966-22.350，p = 0.002) 和低 FoxP3 + Tregs (HR 7.317，95% CI 2.154-24.855, p = 0.001) 是下位 OS 的独立预测因子。使用这两个变量，我们构建了一个新的预后模型，挑出 3 组具有不同的风险特征: 1 组，无不良因素; 2 组，1 个不良因素; 3 组,2 不利因素。组 1 、组 2 、组 3 的 3 年 OS 率分别为 93.3% 、 46.6% 、 20.8% (p<0.001)，3 年 PFS 率分别为 86.7% 、分别为 40.8% 和 15.0% (p = 0.001)。 结论: 本研究首次验证了 ENKTL 中 nPD-L1 和肿瘤浸润 FoxP3 + Tregs 的预后价值; 新的免疫学预后模型可能用于临床试验中对 ENKTL 患者进行分层，以寻求新的治疗策略。
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.