Investigating T Cell Immunity in Cancer: Achievements and Prospects

T cells play a key role in tumour surveillance, both identifying and eliminating transformed cells. However, as tumours become established they form their own suppressive microenvironments capable of shutting down T cell function, and allowing tumours to persist and grow. To further understand the tumour microenvironment, including the interplay between different immune cells and their role in anti-tumour immune responses, a number of studies from mouse models to clinical trials have been performed. In this review, we examine mechanisms utilized by tumour cells to reduce their visibility to CD8⁺ Cytotoxic T lymphocytes (CTL), as well as therapeutic strategies trialled to overcome these tumour-evasion mechanisms. Next, we summarize recent advances in approaches to enhance CAR T cell activity and persistence over the past 10 years, including bispecific CAR T cell design and early evidence of efficacy. Lastly, we examine mechanisms of T cell infiltration and tumour regression, and discuss the strengths and weaknesses of different strategies to investigate T cell function in murine tumour models.     

Adenovirus-Mediated Inducible Expression of a PD-L1 Blocking Antibody in Combination with Macrophage Depletion Improves Survival in a Mouse Model of Peritoneal Carcinomatosis

Immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in a growing number of malignancies. However, overcoming primary or secondary resistances is difficult due to pharmacokinetics issues and side effects associated with high systemic exposure. Local or regional expression of monoclonal antibodies (mAbs) using gene therapy vectors can alleviate this problem. In this work, we describe a high-capacity adenoviral vector (HCA-EFZP-aPDL1) equipped with a mifepristone-inducible system for the controlled expression of an anti-programmed death ligand 1 (PD-L1) blocking antibody. The vector was tested in an immune-competent mouse model of colorectal cancer based on implantation of MC38 cells. A single local administration of HCA-EFZP-aPDL1 in subcutaneous lesions led to a significant reduction in tumor growth with minimal release of the antibody in the circulation. When the vector was tested in a more stringent setting (rapidly progressing peritoneal carcinomatosis), the antitumor effect was marginal even in combination with other immune-stimulatory agents such as polyinosinic-polycytidylic acid (pI:C), blocking mAbs for T cell immunoglobulin, mucin-domain containing-3 (TIM-3) or agonistic mAbs for 4-1BB (CD137). In contrast, macrophage depletion by clodronate liposomes enhanced the efficacy of HCA-EFZP-aPDL1. These results highlight the importance of addressing macrophage-associated immunoregulatory mechanisms to overcome resistance to ICIs in the context of colorectal cancer.     

Immune Checkpoint Inhibitors: A Promising Treatment Option for Metastatic Castration-Resistant Prostate Cancer?

Since 2010, several treatment options have been available for men with metastatic castration-resistant prostate cancer (mCRPC), including immunotherapeutic agents, although the clinical benefit of these agents remains inconclusive in unselected mCRPC patients. In recent years, however, immunotherapy has re-emerged as a promising therapeutic option to stimulate antitumor immunity, particularly with the use of immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 and CTLA-4 inhibitors. There is increasing evidence that ICIs may be especially beneficial in specific subgroups of patients with high PD-L1 tumor expression, high tumor mutational burden, or tumors with high microsatellite instability/mismatch repair deficiency. If we are to improve the efficacy of ICIs, it is crucial to have a better understanding of the mechanisms of resistance to ICIs and to identify predictive biomarkers to determine which patients are most likely to benefit. This review focuses on the current status of ICIs for the treatment of mCRPC (either as monotherapy or in combination with other drugs), mechanisms of resistance, potential predictive biomarkers, and future challenges in the management of mCRPC.     

设置进程检查点的嵌入式容错系统设计

针对嵌入式Linux系统的特点,通过设置检查点(checkpoint)实现ARM平台进程级容错。在检查点工作时,通过/proc文件系统与内核进行交互,实时地获取与进程有关的PID、CPU状态以及内存信息,并保存在存储介质中。当进程出现故障后,将上述与进程有关的状态信息进行恢复,从而实现进程级容错。实验表明,该进程级容错系统有较好的容错能力,极大地缩短了进程恢复的时间。     

一种改进的实时嵌入式系统容错优化方法

容错技术中硬件冗余会产生较高的设计和生产成本.针对该问题,提出一种改进的实时嵌入式系统容错优化方法,基于检查点容错技术综合分析系统故障性能、硬实时任务时间约束和软实时任务的效用函数值.以设计的容错模型为基础,计算系统故障概率保证其在故障最大概率值内,给出硬任务截止时间确定可调度性,并应用改进的禁忌搜索算法获得软任务效用函数最佳值,算法有2种简单的邻节点结构,其禁忌准则遵循邻节点方法禁忌,优化效率明显改善.实验结果表明,该方法可进行故障分析等综合分析,并能迅速获得最大效用函数值.     

资源管理系统中基于作业检查点的自动容错

本文提出了在资源管理系统中基于作业检查点实现自动容错支持,深入分析了作业与任务检查点分离、映像文件管理、自动恢复执行等关键技术。基于BLCR在SLURM中实现了作业的自动检查点/恢复,详细介绍了实现中的关键技术难题。分析与测试表明,检查点与恢复执行功能正确,并能有效缩短大规模作业成功运行所需的时间。     

PD‐1 Blockade for Improving the Antitumor Efficiency of Polymer–Doxorubicin Nanoprodrug

Chemotherapy is well recognized to induce immune responses during some chemotherapeutic drugs‐mediated tumor eradication. Here, a strategy involving blocking programmed cell death protein 1 (PD‐1) to enhance the chemotherapeutic effect of a doxorubicin nanoprodrug HA‐Psi‐DOX is proposed and the synergetic mechanism between them is further studied. The nanoprodrugs are fabricated by conjugating doxorubicin (DOX) to an anionic polymer hyaluronic acid (HA) via a tumor overexpressed matrix metalloproteinase sensitive peptide (CPLGLAGG) for tumor targeting and enzyme‐activated drug release. Once accumulated at the tumor site, the nanoprodrug can be activated to release antitumor drug by tumor overexpressed MMP‐2. It is found that HA‐Psi‐DOX nanoparticles can kill tumor cells effectively and initiate an antitumor immune response, leading to the upregulation of interferon‐γ. This cytokine promotes the expression of programmed cell death protein‐ligand 1 (PD‐L1) on tumor cells, which will cause immunosuppression after interacting with PD‐1 on the surface of lymphocytes. The results suggest that the therapeutic efficiency of HA‐Psi‐DOX nanoparticles is significantly improved when combined with checkpoint inhibitors anti‐PD‐1 antibody (α‐PD1) due to the neutralization of immunosuppression by blocking the interaction between PD‐L1 and PD‐1. This therapeutic system by combining chemotherapy and immunotherapy further increases the link between conventional tumor therapies and immunotherapy.     

嵌入式操作系统进程监测器的设计与实现

为避免嵌入式操作系统的进程受到恶意软件的修改破坏,提出一种适合于嵌入式操作系统的进程监测器。监测器周期性地对系统进程控制块进行检测恢复,通过设置进程检查点为系统提供恢复操作进程,并在Linux上进行实现,给出主要的数据结构和实现过程。实验结果表明,监测器的运行对系统性能影响小,能对系统进程进行有效的检测恢复。     

减少检查点开销的一种方法

设置检查点（ｃｈｅｃｋｐｏｉｎｔｉｎｇ）是容错计算机系统进行故障恢复的重要手段。设置检查点的开销则是影响其性能的一个主要因素。文章提出了一种预先保存部分检查点数据的新方法。该方法不仅能够有效地减少检查点开销,而且具有比较短的检查点延迟。     

A Low-Cost Checkpointing Technique for Distributed Databases

For distributed databases, checkpointing is used to ensure an efficient way to perform global reconstruction. However, the need for global reconstruction is infrequent. Most current checkpointing approaches for distributed databases are too expensive during run time. Some of them allow the checkpointing process to run in parallel with normal transactions at the cost of more data and resource contention, which in turn causes longer response time for normal transactions. Thus, an efficient way to checkpoint distributed databases is needed to avoid degrading the system performance. This paper presents a low-cost solution, called Loosely Synchronized Local Fuzzy Checkpointing (LSLFC), to these problems. LSLFC supports global reconstruction, and our performance study shows that LSLFC has little overhead during run time.