Tianyi Liu, Dan Jin, Son B Le, Dongjiang Chen, Mathew Sebastian, Alberto Riva, Ruixuan Liu, David D Tran
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引用次数: 0
摘要
由于血脑屏障和免疫抑制或 "冷 "肿瘤微环境(TME),免疫疗法对胶质母细胞瘤(GBM)的疗效有限,因为GBM的微环境以免疫抑制细胞为主,细胞毒性T淋巴细胞(CTL)和树突状细胞(DC)匮乏。在此,我们报告了一种机器学习精确方法的开发和应用情况,该方法可识别细胞命运决定因子(CFD),这些细胞命运决定因子可特异性地将 GBM 重编程为具有类似 DC 功能的诱导抗原递呈细胞(iDC-APC)。在小鼠 GBM 模型中,iDC-APC 获得了类似 DC 的形态、调控基因表达谱以及与天然 DC 类似的功能。这些获得的功能包括吞噬、直接呈现内源性抗原和交叉呈现外源性抗原。后者赋予了 iDC-APCs 为天真 CD8+ CTLs 提供能量的能力,这是一种对抗肿瘤免疫至关重要的 DC 标志性功能。瘤内 iDC-APCs 仅在免疫功能正常的动物中能减少肿瘤生长并提高存活率,这与 CD4+ T 细胞和活化的 CD8+ CTL 在 TME 中的广泛浸润相吻合。重新激活的TME与肿瘤内可溶性PD-1诱饵免疫疗法和基于DC的GBM疫苗协同作用,使肿瘤特异性CD8+ CTL对高度耐药的GBM细胞产生强大的杀伤力,并显著延长了生存期。最后,我们定义了一种独特的CFD组合,专门用于人类GBM向胶质瘤干样细胞(GSC)和非GSC GBM细胞的iDC-APC转换,证实了计算定向、肿瘤特异性转换免疫疗法对GBM和潜在的其他实体瘤的临床实用性。
Machine Learning-Directed Conversion of Glioblastoma Cells to Dendritic Cell-like Antigen-Presenting Cells as Cancer Immunotherapy.
Immunotherapy has limited efficacy in glioblastoma (GBM) due to the blood-brain barrier and the immunosuppressed or "cold" tumor microenvironment (TME) of GBM, which is dominated by immune-inhibitory cells and depleted of cytotoxic T lymphocytes (CTL) and dendritic cells (DC). Here, we report the development and application of a machine-learning precision method to identify cell fate determinants (CFD) that specifically reprogram GBM into induced antigen-presenting cells with DC-like functions (iDC-APC). In murine GBM models, iDC-APCs acquired DC-like morphology, regulatory gene expression profile, and functions comparable to natural DCs. Among these acquired functions were phagocytosis, direct presentation of endogenous antigens, and cross presentation of exogenous antigens. The latter endowed the iDC-APCs with the ability to prime naïve CD8+ CTLs, a hallmark DC function critical for antitumor immunity. Intratumor iDC-APCs reduced tumor growth and improved survival only in immunocompetent animals, which coincided with extensive infiltration of CD4+ T cells and activated CD8+ CTLs in the TME. The reactivated TME synergized with an intratumor soluble PD-1 decoy immunotherapy and a DC-based GBM vaccine, resulting in robust killing of highly resistant GBM cells by tumor-specific CD8+ CTLs and significantly extended survival. Lastly, we defined a unique CFD combination specifically for the human GBM to iDC-APC conversion of both glioma stem-like cells (GSC) and non-GSC GBM cells, confirming the clinical utility of a computationally directed, tumor-specific conversion immunotherapy for GBM and potentially other solid tumors.
期刊介绍:
Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes.
Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.