Clinical significance of tumour mutation burden in immunotherapy across multiple cancer types: an individual meta-analysis.
- 作者列表："Yang Z","Wei S","Deng Y","Wang Z","Liu L
BACKGROUND:Biomarkers for stratifying patients that could benefit from immune checkpoint inhibitors are necessary. Tumour mutation burden has recently become a promising biomarker in cancer, but the associations between tumour mutation burden and outcomes of immune checkpoint inhibitors treatment were not well-documented in present studies. METHODS:We searched PubMed, Web of Science and EMBASE databases up to 1 October 2019. Studies evaluated the association between tumour mutation burden and clinical outcomes were included. Hazard ratios and odds ratios were applied to estimate the association of tumour mutation burden score with overall survival, progression-free survival and response rate, respectively. The best cut-off value was chosen by best discriminated overall survival using Contal and O'Quigley method. RESULTS:Twenty-two studies involving 6171 patients in diverse cancers were included. The individual participant data meta-analysis demonstrated that high tumour mutation burden was associated with better overall survival (HR = 0.57, 95% CI = 0.50-0.64) and progression-free survival (HR = 0.50, 95% CI = 0.40-0.63) and higher response rate. The best cut-off values in each cancer type were 17.7/MB in non-small cell lung cancer, 7.9/MB in bladder cancer, 6.1/MB in melanoma, 12.3/MB in colorectal cancer, 6.9/MB in esophagogastric cancer, 10.5/MB in head and neck cancer. The pooled meta-analysis showed the prognosis value was robust and the sensitivity, specificity and area under the receiver operating characteristic curves in predicting response rates were 0.63, 0.71 and 0.73, respectively. CONCLUSIONS:The present meta-analysis indicates tumour mutation burden is a promising predictor of immune checkpoint inhibitors therapy but the cut-off value differs in different cancers.
背景: 对可能受益于免疫检查点抑制剂的患者进行分层的生物标志物是必要的。肿瘤突变负荷最近已经成为癌症中一个有前途的生物标志物，但是肿瘤突变负荷与免疫检查点抑制剂治疗结果之间的相关性在目前的研究中没有得到很好的记录。 方法: 我们检索了截至 2019 年 10 月 1 日的 PubMed 、 Web of Science 和 EMBASE 数据库。纳入了评价肿瘤突变负荷与临床结局之间相关性的研究。应用风险比和优势比分别估计肿瘤突变负荷评分与总生存期、无进展生存期和反应率的相关性。使用 Contal 和 o 'quigley 方法通过最佳判别总生存期选择最佳临界值。 结果: 纳入 22 项研究，包括 6171 例不同癌症患者。个体参与者数据荟萃分析表明，高肿瘤突变负荷与更好的总生存期相关 (HR = 0.57，95% CI = 0.50-0.64) 和无进展生存期 (HR = 0.50，95% CI = 0.40-0.63) 和较高的反应率。每种癌症类型的最佳临界值非小细胞肺癌为 17.7/MB，膀胱癌为 7.9/MB，黑色素瘤为 6.1/MB,结直肠癌 12.3/MB，食管胃癌 6.9/MB，头颈癌 10.5/MB。合并荟萃分析显示预后价值稳健，预测缓解率的敏感性、特异性和受试者工作特征曲线下面积分别为 0.63 、 0.71 和 0.73。 结论: 目前的荟萃分析表明肿瘤突变负荷是免疫检查点抑制剂治疗的一个有前途的预测因子，但不同癌症的临界值不同。
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.