Immune-mediated anti-tumor effects of metformin; targeting metabolic reprogramming of T cells as a new possible mechanism for anti-cancer effects of metformin.
二甲双胍的免疫介导抗肿瘤作用; 靶向 T 细胞的代谢重编程作为二甲双胍抗癌作用的新的可能机制。
- 作者列表："Bahrambeigi S","Shafiei-Irannejad V
:Immunotherapy-based cancer treatment has revolutionized the era of cancer patients recuperation and it has brought a strong hope to treatment of some types of cancers. Metformin, a widely used antidiabetic drug, which has intensely been studied for its anticancer effects, is believed to have positive influences on immune responses against tumor cells. Metformin can affect metabolic pathways within cells mainly through activation of AMPK. Metabolic restriction of tumor microenvironment on effector immune cells is one of the important strategies favoring tumor cells to escape from immunogenic cell death. The metabolism of T cells has an axial role in shaping and supporting immune responses and may have an important role in anticancer immunity, suggesting that the functionality and durability of tumor-specific T cells need sufficient energy and nutrients. Energy biogenesis of tumor-specific cytotoxic T cells has become an interesting field of study and it is suggested that activation and maintenance of effector T cell responses in tumor microenvironment may occur by metabolic reprogramming of T cells. AMPK has been noticed as the main intracellular energy sensor and mitochondrial biogenesis key regulator which can control and regulate metabolic reprogramming in immune cells and increase antitumor immunity. Metabolic reprogramming of T cells to overcome metabolic restriction in tumor microenvironment, maiming effector T cell responses against tumor cells, has been noticed by several studies. Here we represent metformin, an AMPK activator, as a new candidate drug for metabolic reprogramming of tumor-specific T cells to increase the efficacy and accountability of cancer immunotherapy.
: 基于免疫治疗的癌症治疗彻底改变了癌症患者康复的时代，并为某些类型的癌症治疗带来了强烈的希望。二甲双胍是一种广泛使用的抗糖尿病药物，其抗癌作用已被深入研究，被认为对抗肿瘤细胞的免疫反应有积极的影响。二甲双胍主要通过激活 AMPK 影响细胞内的代谢途径。肿瘤微环境对效应免疫细胞的代谢限制是有利于肿瘤细胞逃避免疫原性细胞死亡的重要策略之一。T 细胞的代谢具有塑造和支持免疫反应的轴向作用，可能在抗癌免疫中具有重要作用,提示肿瘤特异性 T 细胞的功能性和持久性需要足够的能量和营养物质。肿瘤特异性细胞毒性 T 细胞的能量生物合成已成为一个有趣的研究领域，提示肿瘤微环境中效应 T 细胞反应的激活和维持可能通过 T 细胞的代谢重编程发生。。AMPK 作为主要的细胞内能量传感器和线粒体生物合成关键调控因子，可以控制和调节免疫细胞中的代谢重编程，增加抗肿瘤免疫。T 细胞的代谢重编程以克服肿瘤微环境中的代谢限制，削弱针对肿瘤细胞的效应 T 细胞应答，已经被一些研究注意到。在这里，我们代表了 AMPK 激活剂二甲双胍，作为肿瘤特异性 T 细胞代谢重编程的新候选药物，以增加癌症免疫治疗的疗效和问责制。
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.