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Immune checkpoint inhibitors:breakthroughs in cancer treatment

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Cancer Biology & Medicine 2024年第6期21卷 451-472页

作者： Xueqing Kong Jinyi Zhang Shuwei Chen Xianyang Wang Qing Xi Han Shen Rongxin Zhang Laboratory of Immunology and Inflammation School of Life Sciences and Biopharmaceutics Guangdong Pharmaceutical University Department of Biology School of Life Sciences and Biopharmaceutics Guangdong Pharmaceutical University

Over the past two decades, immunotherapies have increasingly been considered as first-line treatments for most cancers. One such treatment is immune checkpoint blockade(ICB), which has demonstrated promising results against various solid tumors in clinical trials. Monoclonal antibodies(mAbs) are currently available as immune checkpoint inhibitors(ICIs). These ICIs target specific immune checkpoints, including cytotoxic T-lymphocyte-associated antigen-4(CTLA-4) and programmed cell death protein 1(PD-1). Clinical trial results strongly support the feasibility of this immunotherapeutic approach. However, a substantial proportion of patients with cancer develop resistance or tolerance to treatment, owing to tumor immune evasion mechanisms that counteract the host immune response.Consequently, substantial research focus has been aimed at identifying additional ICIs or synergistic inhibitory receptors to enhance the effectiveness of anti-PD-1, anti-programmed cell death ligand 1(anti-PD-L1), and anti-CTLA-4 treatments. Recently, several immune checkpoint molecular targets have been identified, such as T cell immunoreceptor with Ig and ITIM domains(TIGIT), mucin domain containing-3(TIM-3), lymphocyte activation gene-3(LAG-3), V-domain immunoglobulin suppressor of T cell activation(VISTA), B and T lymphocyte attenuator(BTLA), and signal-regulatory protein α(SIRPα). Functional m Abs targeting these molecules are under development. CTLA-4, PD-1/PD-L1, and other recently discovered immune checkpoint proteins with distinct structures are at the forefront of research. This review discusses these structures, as well as clinical progress in m Abs targeting these immune checkpoint molecules and their potential applications.

关键词： CTLA-4 ICIs Immunotherapy PD-1 cancer

Impact of tourism on the vigilance behavior of the Cyprus rock agama(Laudakia cypriaca)

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Integrative Zoology 2024年第3期19卷 577-583页

作者： Artur GOLAWSKI Iris CHARALAMBIDOU Sylwia GOLAWSKA Faculty of sciences Siedlce University of Natural Sciences and HumanitiesSiedlcePolandand Department of life sciences School of Life and Health SciencesUniversity of NicosiaNicosiaCyprus

Escape behavior is a common antipredator strategy among wild animals.Here,we investigated the effect of four factors on the vigilance behavior of the endemic Cyprus rock agama(Laudakia cypriaca).Flight initiation distance(FID,the minimum distance to which an observer can approach a lizard before it flees)was measured in relation to the type of location(tourist vs.nontourist area),the observer’s starting distance,air temperature,and substrate temperature.We collected data for 39 agamas in tourist areas and 34 of these lizards in nontourist areas.As a whole,the mean starting distance was 10.5 m and the FID was 3.6 m.The average substrate temperature was 34.0℃ and the average air temperature 29.6℃.Only the type of area affected the agamas’escape decisions with FID being 1.8 m shorter in tourist areas than in nontourist areas(2.7 m vs.4.5 m).This is probably due to the habituation of lizards to the presence of humans in the former areas.This study shows that tourism strongly affects the behavior of lizards,which may have consequences for the functioning of the population.Tourists can increase the safety of lizards by creating a human shield to deter predators.Once the tourist season is over,lizards may become more vulnerable to predators.

关键词： anthropogenic disturbance flight initiation distance lizards tourism vigilance behavior

PRRSV degrades MDA5 via dual autophagy receptors P62 and CCT2 to evade antiviral innate immunity

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Virologica Sinica 2024年第2期39卷 264-276页

作者： Ruiqi Sun Yanyu Guo Lilin Zhang Huixia Zhang Boxuan Yin Xiaoyang Li Changyan Li Liu Yang Lei Zhang Zexing Li Jinhai Huang school of life sciences Tianjin UniversityTianjin300072China

Porcine reproductive and respiratory syndrome virus(PRRSV)is a major economically devastating pathogen that has evolved various strategies to evade innate immunity.Downregulation of antiviral interferon largely promotes PRRSV immunoevasion by utilizing cytoplasmic melanoma differentiation-associated gene 5(MDA5),a receptor that senses viral RNA.In this study,the downregulated transcription and expression levels of porcine MDA5 in PRRSV infection were observed,and the detailed mechanisms were explored.We found that the interaction between P62 and MDA5 is enhanced due to two factors:the phosphorylation modification of the autophagic receptor P62 by the upregulated kinase CK2αand the K63 ubiquitination of porcine MDA5 catalyzed by the E3 ubiquitinase TRIM21 in PRRSV-infected cells.As a result of these modifications,the classic P62-mediated autophagy is triggered.Additionally,porcine MDA5 interacts with the chaperonin containing TCP1 subunit 2(CCT2),which is enhanced by PRRSV nsp3.This interaction promotes the aggregate formation and autophagic clearance of MDA5-CCT2-nsp3 independently of ubiquitination.In summary,enhanced MDA5 degradation occurs in PRRSV infection via two autophagic pathways:the binding of MDA5 with the autophagy receptor P62 and the aggrephagy receptor CCT2,leading to intense innate immune suppression.The research reveals a novel mechanism of immune evasion in PRRSV infection and provides fundamental insights for the development of new vaccines or therapeutic strategies.

关键词： Porcine reproductive and respiratory syndrome virus(PRRSV) nsp3 Autophagy MDA5

Tributyltin causes generational neurodevelopmental toxicity and the protective effect of folic acid in zebrafish

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Journal of Environmental sciences 2024年第3期137卷 615-625页

作者： Haoxing Cai Naying Zheng Chen Tang Yuxuan Zhang Zhenghong Zuo Chengyong He State Key Laboratory of Cellular Stress Biology School of Life SciencesFaculty of Medicine and Life SciencesXiang’an Hospital of Xiamen UniversityXiamen UniversityXiamen 361005China

Tributyltin(TBT),a common organotin environmental pollutant,may pose a threat to human development during critical early-life periods.We aimed to assess the neurodevelopmental intergenerational toxicity of early-life exposure to TBT and the protective effect of DNA methyl donor folic acid(FA).Specifically,after early-life exposure(1–21 days postfertilization,dpf)to TBT(0,1,10 and 100 ng/L),zebrafish(Danio rerio)were cultured in clean medium until sexual maturity.The exposed females were mated with unexposed males to produce embryos(F1).The F1 generation were cultured(4–120 hours post-fertilization,hpf)with and without 1 mmol/L FA.The neurotoxic effects of early-life TBT exposure for zebrafish and their offspring(F1)were significantly enhanced anxiety and reduced aggression,decreased gene expression of DNA methyltransferase in the brain and increased serotonin levels in the body.Moreover,the intergenerational neurodevelopmental toxicity,as manifested in the F1 generation,was attenuated by FA supplementation.In summary,early-life TBT exposure led to intergenerational neurodevelopmental deficits in zebrafish,and DNA methyl donors had a protective effect on F1 neurodevelopment,which can inform the prevention and treatment of intergenerational neurotoxicity due to organotin pollutants.

关键词： Tributyltin Neurodevelopment Intergeneration DNA methylation Folic acid Zebrafish

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Implications of mosquito metabolism on vector competence

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Insect Science 2024年第3期31卷 674-682页

作者： Li Gao Wenxu Yang Jingwen Wang State Key Laboratory of Genetic Engineering School of Life SciencesFudan UniversityShanghaiChina Ministry of Education Key Laboratory of Contemporary Anthropology School of Life SciencesFudan UniversityShanghaiChina

Mosquito-borne diseases(MBDs)annually kill nearly half a million people.Due to the lack of effective vaccines and drugs on most MBDs,disease prevention relies primarily on controlling mosquitoes.Despite huge efforts having been put into mosquito control,eco-friendly and sustainable mosquito-control strategies are still lacking and urgently demanded.Most mosquito-transmitted pathogens have lost the capacity of de novo nutrition biosynthesis,and rely on their vertebrate and invertebrate hosts for sustenance during the long-term obligate parasitism process.Therefore,a better understanding of the metabolic interactions between mosquitoes and pathogens will contribute to the discovery of novel metabolic targets or regulators that lead to reduced mosquito populations or vector competence.This review summarizes the current knowledge about the effects of mosquito metabolism on the transmission of multiple pathogens.We also discuss that research in this area remains to be explored to develop multiple biological prevention and control strategies for MBDs.

关键词： flaviviruses mosquito metabolism Plasmodium vector competence

How variable progenitor clones construct a largely invariant neocortex

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National Science Review 2024年第1期11卷 129-144页

作者： Zhongfu Shen Jiajun Yang Qiangqiang Zhang Kuiyu Wang Xiaohui Lv Xiaolin Hu Jian Ma Song-Hai Shi New Cornerstone Science Laboratory IDG/McG overn Institute for Brain Research Tsinghua-Peking Center for Life Sciences Beijing Frontier Research Center for Biological Structure School of Life Sciences Tsinghua University Department of Computer sciences Tsinghua University College of life sciences Nankai University Chinese Institute for Brain Research

The neocortex contains a vast collection of diverse neurons organized into distinct layers. While nearly all neocortical neurons are generated by radial glial progenitors(RGPs), it remains largely unclear how a complex yet organized neocortex is constructed reliably and robustly. Here, we show that the division behavior and neuronal output of RGPs are highly constrained with patterned variabilities to support the reliable and robust construction of the mouse neocortex. The neurogenic process of RGPs can be well-approximated by a consistent Poisson-like process unfolding over time, producing deep to superficial layer neurons progressively. The exact neuronal outputs regarding layer occupation are variable; yet, this variability is constrained systematically to support all layer formation, largely reflecting the variable intermediate progenitor generation and RGP neurogenic entry and exit timing differences. Together, these results define the fundamental features of neocortical neurogenesis with a balanced reliability and variability for the construction of the complex neocortex.

关键词： neocortex radial glial progenitor intermediate progenitor neurogenesis clonal variability layer formation

Exploring lysosomal biology: current approaches and methods

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Biophysics Reports 2024年第2期10卷 111-120页

作者： Qiuyuan Yin Chonglin Yang State Key Laboratory of Conservation and Utilization of Bio-resources in Yunnan and Center for life sciences School of Life Sciences Yunnan University Southwest United Graduate school

Lysosomes are the degradation centers and signaling hubs in the cell. Lysosomes undergo adaptation to maintain cell homeostasis in response to a wide variety of cues. Dysfunction of lysosomes leads to aging and severe diseases including lysosomal storage diseases(LSDs), neurodegenerative disorders,and cancer. To understand the complexity of lysosome biology, many research approaches and tools have been developed to investigate lysosomal functions and regulatory mechanisms in diverse experimental systems. This review summarizes the current approaches and tools adopted for studying lysosomes, and aims to provide a methodological overview of lysosomal research and related fields.

关键词： Lysosome Method Cultured cell C. elegans Mice

Females adopt sexual catalepsy to facilitate mating

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Current Zoology 2024年第2期70卷 174-181页

作者： Jihe Liu Keke Liu Yu Tang Weihua Wang Xiang Xu Jianhui Liang Yonghong Xiao Mark A.Elgar College of life sciences Jinggangshan UniversityJi'anJiangxi 343009China Pharmaceutical Center Tsinghua UniversityBeijing 100084China College of life sciences Hunan Normal UniversityChangshaHunan 410081China school of Pharmaceutical sciences Peking UniversityBeijing 100083China school of Biosciences University of MelbourneMelbourneVictoria 3010Australia school of life sciences and Technology Tongii UniversityShanghai 200092China

Theory predicts that males and females of dioecious species typically engage in an evolutionary sexual conflict over the frequency and choice of mating partner.Female sexual cannibalism,a particularly dramatic illustration of this conflict,is widespread in certain animal taxa including spiders.Nevertheless,females of some funnel weaving spiders that are generally aggressive to conspecifics enter a cataleptic state after male courtship,ensuring the males can mate without risk of attack.In this study,we demonstrated that the physical posture and duration,metabo-lites,and central neurotransmitters of females of Aterigena aculeata in sexual catalepsy closely resemble females in thanatosis but are distinct from those in anesthesia,indicating that the courted females feign death to eliminate the risk of potentially aggressive responses and thereby allow preferred males to mate.Unlike the taxonomically widespread thanatosis,which generally represents a deceptive visual signal that acts against the interest of the receivers,sexual catalepsy of females in the funnel weaving spiders may deliver a sexual-receptive signal to the courting males and thereby benefit both the signal senders and receivers.Therefore,sexual catalepsy in A.aculeata may not reflect a conflict butrather a confluence of interest betweenthe sexes.

关键词： female catalepsy funnel weaving spiders mate choice mating strategy sexual behavior.

Hemin blocks TIGIT/PVR interaction and induces ferroptosis to elicit synergistic effects of cancer immunotherapy

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Science China(life sciences) 2024年第5期67卷 996-1009页

作者： Xiaowen Zhou Yang Li Xiangrui Zhang Beibei Li Shengzhe Jin Menghan Wu Xiuman Zhou Qingyu Dong Jiangfeng Du Wenjie Zhai Yahong Wu Lu Qiu Guodong Li Yuanming Qi Wenshan Zhao Yanfeng Gao school of life sciences Zhengzhou UniversityZhengzhou 450001China school of Pharmaceutical sciences(Shenzhen) Shenzhen Campus of Sun Yat-sen UniversityShenzhen 518107China

The immune checkpoint TIGIT/PVR blockade exhibits significant antitumor effects through activation of NK and CD8^(+)T cell-mediated cytotoxicity.Immune checkpoint blockade(ICB)could induce tumor ferroptosis through IFN-γreleased by immune cells,indicating the synergetic effects of ICB with ferroptosis in inhibiting tumor growth.However,the development of TIGIT/PVR inhibitors with ferroptosis-inducing effects has not been explored yet.In this study,the small molecule Hemin that could bind withTIGIT to block TIGIT/PVR interaction was screened by virtual molecular docking and cell-based blocking assay.Hemin could effectively restore the IL-2 secretion from Jurkat-hTIGIT cells.Hemin reinvigorated the function of CD8^(+)T cells to secrete IFN-γand the elevated IFN-γcould synergize with Hemin to induce ferroptosis in tumor cells.Hemin inhibited tumor growth by boosting CD8^(+)T cell immune response and inducing ferroptosis in CT26 tumor model.More importantly,Hemin in combination with PD-1/PD-L1 blockade exhibited more effective antitumor efficacy in anti-PD-1 resistant B16 tumor model.In summary,our finding indicated that Hemin blocked TIGIT/PVR interaction and induced tumor cell ferroptosis,which provided a new therapeutic strategy to combine immunotherapy and ferroptosis for cancer treatment.

关键词： cancer immunotherapy TIGIT/PVR small molecule Hemin ferroptosis

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