High expression of PD-L1 mainly occurs in non-small cell lung cancer patients with squamous cell carcinoma or poor differentiation

Background:Lung cancer is one of the most lethal cancers worldwide,but studies have shown that the higher the expression of programmed cell death protein 1 ligand 1(PD-L1)in non-small cell lung cancer(NSCLC),the more likely it will benefit from anti-PD-L1 immunotherapy.The purpose of our study was to collect and analyze abundant clinical samples in order to provide evidence for clinicians and patients who might consider anti-PD-L1 immunotherapy while jointly formulating treatment plans.Methods:On the one hand,we obtained cases from The Cancer Genome Atlas(TCGA)database,including 498 lung squamous cell cancer(LUSC)patients and 515 lung adenocarcinoma(LUAD)patients.We studied the lung caner driver gene in LUSC and LUAD.On the other hand,PD-L1 expression was detected in lung cancer tissues of 1,008 NSCLC patients with immunohistochemistry staining(IHC),and we studied the correlation between PD-L1 protein expression and clinicopathological characteristics.Results:PD-L1 expression was higher in LUSC than in LUAD at the mRNA level.In univariate analysis,PD-L1 expression at the protein level was higher in patients who were males,were LUSC,were smokers,had a tumor diameter>3 cm,had poor differentiation,or had stages Ⅲ-Ⅳ disease.In multivariate analysis,PD-L1 expression was higher in patients who were LUSC or in poor differentiation.Conclusion:In term of protein level,PD-L1 expression was higher in NSCLC patients who were LUSC or in poor differentiation.We recommend that PD-L1 IHC detection can be routinely performed in such populations that are likely to benefit most from PD-L1 immunotherapy.

Chromatin remodeling factor lymphoid.specific helicase inhibits ferroptosis through lipid metabolic genes in lung cancer progression

Ferroptosis, a novel mode of non-apoptotic cell death,involves a metabolic dysfunction that results in the production of iron-dependent reactive oxygen species (ROS),an iron carrier protein (transferrin), intracellular metabolic process, and related regulators (e.g., p53 protein).Previous studies have linked ferroptosis with oncogenic Ras [1], and p53 tumor suppressor positively regulates ferroptosis by transcriptionally inhibiting the expression of the cysteine/glutamate antiporter, which is encoded by the SLC7A11 gene in human [1, 2]. Whether other factors such as epigenetic factors are involved in the process remains less known.Chromatin modifier lymphoid specific helicase (LSH)contributes to the malignant progression of nasopharyngeal carcinoma and glioma [3]. We recently indicated that LSH was shown to co-operate with partners, such as G9a, to drive cancer progression [4, 5].

GPR162 activates STING dependent DNA damage pathway as a novel tumor suppressor and radiation sensitizer

In the treatment of most malignancies,radiotherapy plays a significant role.However,the resistance of cancer cells to ionizing radiation(IR)is the main reason for the failure of radiotherapy,which causes tumor recurrence and metastasis.In this study,we confirmed that GPR162,an orphan receptor in the G-protein-coupled receptor family,acted as a novel radiotherapy sensitizer by interacting with the stimulator of interferon genes(STING),which targeted DNA damage responses,activated IRF3,accelerated the activation of type I interferon system,promoted the expression of chemokines including CXCL10 and CXCL4,and inhibited the occurrence and development of tumors.Interestingly,the activation of STING by overexpression of GPR162 was independent of the classical pathway of cGAS.STING inhibitors could resist the antitumor effect of overexpression of GPR162 in IR-induced mouse models.In addition,most solid tumors showed low expression of GPR162.And the higher expression of GPR162 indicated a better prognosis in patients with lung adenocarcinoma,liver cancer,breast cancer,etc.In summary,these results suggested that GPR162 may serve as a potential sensitizer of radiotherapy by promoting radiotherapy-induced STING-IFN production and increasing the expression of chemokines including CXCL10 and CXCL4 in DNA damage response,providing an alternative strategy for improving cancer radiotherapy.

Signaling pathways in cancer metabolism:mechanisms and therapeutic targets

A wide spectrum of metabolites(mainly,the three major nutrients and their derivatives)can be sensed by specific sensors,then trigger a series of signal transduction pathways and affect the expression levels of genes in epigenetics,which is called metabolite sensing.Life body regulates metabolism,immunity,and inflammation by metabolite sensing,coordinating the pathophysiology of the host to achieve balance with the external environment.Metabolic reprogramming in cancers cause different phenotypic characteristics of cancer cell from normal cell,including cell proliferation,migration,invasion,angiogenesis,etc.Metabolic disorders in cancer cells further create a microenvironment including many kinds of oncometabolites that are conducive to the growth of cancer,thus forming a vicious circle.At the same time,exogenous metabolites can also affect the biological behavior of tumors.Here,we discuss the metabolite sensing mechanisms of the three major nutrients and their derivatives,as well as their abnormalities in the development of various cancers,and discuss the potential therapeutic targets based on metabolite-sensing signaling pathways to prevent the progression of cancer.

Effects of radiation therapy on tumor microenvironment:an updated review

Cancer is a major threat to human health and causes death worldwide.Research on the role of radiotherapy(RT)in the treatment of cancer is progressing;however,RT not only causes fatal DNA damage to tumor cells,but also affects the interactions between tumor cells and different components of the tumor microenvironment(TME),including immune cells,fibroblasts,macrophages,extracellular matrix,and some soluble products.Some cancer cells can survive radiation and have shown strong resistance to radiation through interaction with the TME.Currently,the complex relationships between the tumor cells and cellular components that play major roles in various TMEs are poorly understood.This review explores the relationship between RT and cell-cell communication in the TME from the perspective of immunity and hypoxia and aims to identify new RT biomarkers and treatment methods in lung cancer to improve the current status of unstable RT effect and provide a theoretical basis for further lung cancer RT sensitization research in the future.

Author Correction:GPR162 activates STING dependent DNA damage pathway as a novel tumor suppressor and radiation sensitizer

Since the publication of this article,we noticed a minor mistake in the article that needs to be corrected.We have checked the original data;the correct data are provided in this Corrigendum as follows.The key findings of the article are not affected by these corrections.

Exosomes:key players in cancer and potential therapeutic strategy

Exosomes are extracellular vesicles secreted by most eukaryotic cells and participate in intercellular communication.The components of exosomes,including proteins,DNA,mRNA,microRNA,long noncoding RNA,circular RNA,etc.,which play a crucial role in regulating tumor growth,metastasis,and angiogenesis in the process of cancer development,and can be used as a prognostic marker and/or grading basis for tumor patients.Hereby,we mainly summarized as followed:the role of exosome contents in cancer,focusing on proteins and noncoding RNA;the interaction between exosomes and tumor microenvironment;the mechanisms that epithelial-mesenchymal transition,invasion and migration of tumor affected by exosomes;and tumor suppression strategies based on exosomes.Finally,the application potential of exosomes in clinical tumor diagnosis and therapy is prospected,which providing theoretical supports for using exosomes to serve precise tumor treatment in the clinic.

Demystifying the manipulation of host immunity, metabolism, and extraintestinal tumors by the gut microbiome

The trillions of microorganisms in the gut microbiome have attracted much attention recently owing to their sophisticated and widespread impacts on numerous aspects of host pathophysiology.Remarkable progress in large-scale sequencing and mass spectrometry has increased our understanding of the influence of the microbiome and/or its metabolites on the onset and progression of extraintestinal cancers and the efficacy of cancer immunotherapy.Given the plasticity in microbial composition and function,microbial-based therapeutic interventions,including dietary modulation,prebiotics,and probiotics,as well as fecal microbial transplantation,potentially permit the development of novel strategies for cancer therapy to improve clinical outcomes.Herein,we summarize the latest evidence on the involvement of the gut microbiome in host immunity and metabolism,the effects of the microbiome on extraintestinal cancers and the immune response,and strategies to modulate the gut microbiome,and we discuss ongoing studies and future areas of research that deserve focused research efforts.

Regulating tumor suppressor genes:post-translational modifications

Tumor suppressor genes cooperate with each other in tumors.Three important tumor suppressor proteins,retinoblastoma(Rb),p53,phosphatase,and tensin homolog deleted on chromosome ten(PTEN)are functionally associated and they regulated by posttranslational modification(PTMs)as well.PTMs include phosphorylation,SUMOylation,acetylation,and other novel modifications becoming growing appreciated.Because most of PTMs are reversible,normal cells use them as a switch to control the state of cells being the resting or proliferating,and PTMs also involve in cell survival and cell cycle,which may lead to abnormal proliferation and tumorigenesis.Although a lot of studies focus on the importance of each kind of PTM,further discoveries shows that tumor suppressor genes(TSGs)form a complex“network”by the interaction of modification.Recently,there are several promising strategies for TSGs for they change more frequently than carcinogenic genes in cancers.We here review the necessity,characteristics,and mechanisms of each kind of post-translational modification on Rb,p53,PTEN,and its influence on the precise and selective function.We also discuss the current antitumoral therapies of Rb,p53 and PTEN as predictive,prognostic,and therapeutic target in cancer.

The deubiquitylase UCHL3 maintains cancer stem-like properties by stabilizing the aryl hydrocarbon receptor

Cancer stem cells(CSCs)exhibit highly aggressive and metastatic features and resistance to chemotherapy and radiotherapy.Aryl hydrocarbon receptor(AhR)expression varies among non-small cell lung cancers(NSCLCs),and the mechanisms that support abnormal AhR expression in CSCs remain elusive.Here,we identified ubiquitin carboxyl terminal hydrolase L3(UCHL3),a DUB enzyme in the UCH protease family,as a bona fide deubiquitylase of the AhR in NSCLC.UCHL3 was shown to interact with,deubiquitylate,and stabilize AhR in a manner dependent on its deubiquitylation activity.Moreover,we showed that UCHL3 promotes the stem-like characteristics and potent tumorigenic capacity of NSCLC cells.UCHL3 increased AhR stability and the binding of AhR to the promoter regions of the“stemness”genes ATP-binding cassette subfamily G member 2(ABCG2),KLF4,and c-Myc.Depletion of UCHL3 markedly downregulated the“stemness”genes ABCG2,KLF4,and c-Myc,leading to the loss of selfrenewal and tumorigenesis in NSCLCs.Furthermore,the UCHL3 inhibitor TCID induced AhR degradation and exhibited significantly attenuated efficacy in NSCLC cells with stem cell-like properties.Additionally,UCHL3 was shown to indicate poor prognosis in patients with lung adenocarcinoma.In general,our results reveal that the UCHL3 deubiquitylase is pivotal for AhR protein stability and a potential target for NSCLC-targeted therapy.

IL4I1-driven AHR signature: a new avenue for cancer therapy

Aryl hydrocarbon receptor(AHR)was considered to be an important pan-tumor therapeutic target,but small molecule inhibitors targeting AHR target gene ID01 have failed in clinical trials.The recent paper published in Cell by Opitz et al.explained the failure of previous clinical trials and identified new therapeutic targets(Fig.1).

The cross-talk between methylation and phosphorylation in lymphoid-specific helicase drives cancer stem-like properties

Posttranslational modifications(PTMs)of proteins,including chromatin modifiers,play crucial roles in the dynamic alteration of various protein properties and functions including stem-cell properties.However,the roles of Lymphoid-specific helicase(LSH),a DNA methylation modifier,in modulating stem-like properties in cancer are still not clearly clarified.Therefore,exploring PTMs modulation of LSH activity will be of great significance to further understand the function and activity of LSH.Here,we demonstrate that LSH is capable to undergo PTMs,including methylation and phosphorylation.The arginine methyltransferase PRMT5 can methylate LSH at R309 residue,meanwhile,LSH could as well be phosphorylated by MAPK1 kinase at S503 residue.We further show that the accumulation of phosphorylation of LSH at S503 site exhibits downregulation of LSH methylation at R309 residue,which eventually promoting stem-like properties in lung cancer.Whereas,phosphorylation-deficient LSH S503A mutant promotes the accumulation of LSH methylation at R309 residue and attenuates stem-like properties,indicating the critical roles of LSH PTMs in modulating stem-like properties.Thus,our study highlights the importance of the crosstalk between LSH PTMs in determining its activity and function in lung cancer stem-cell maintenance.

Rab22a-NeoF1:a promising target for osteosarcoma patients with lung metastasis

Osteosarcoma is the most common primary malignant bone tumor among adolescents and children,with high level of lung metastasis and poor prognosis.The treatment of metastatic cases remains a challenge in the clinic,leading to the dramatically decreased survival rate.However,the molecular mechanisms are still unclear.A recent article by Kang et al.demonstrated how chromosomal translocations in osteosarcoma facilitated lung metastasis,and shed new light on its therapeutic strategies1(Fig.1).