Biomarkers for predicting efficacy of chimeric antigen receptor T cell therapy and their detection methods

Cancer immunotherapy has emerged as the fourth most prevalent approach to tumor treatment,alongside surgery,radiotherapy,and chemotherapy.After several decades of development,chimeric antigen receptor T(CAR-T)cell therapy,a promising branch of adoptive T-cell therapy,has demonstrated superior efficacy and safety in comparison to other cell therapies in the treatment of cancer.At present,CAR-T cells are predominantly used to treat hematological malignancies,although their application in solid tumors is being readily investigated.Although numerous studies have examined the biomarkers associated with the safety of CAR-T cell therapy,few have evaluated predictors of CAR-T cell therapeutic efficacy.Thus,the primary objective of this review article was to provide a comprehensive overview of the factors predicting the efficacy of CAR-T cell therapy,with a particular focus on biomarkers and their detection methods.

Hepatocyte nuclear factor 1A suppresses innate immune response by inducing degradation of TBK1 to inhibit steatohepatitis

Non-alcoholic steatohepatitis(NASH),a progressive form of non-alcoholic fatty liver disease(NAFLD),is characterised by chronic liver inflammation,which can further prog-ress into complications such as liver cirrhosis and NASH-associated hepatocellular carcinoma(HCC)and therefore has become a growing health problem worldwide.The type I interferon(IFN)signaling pathway plays a pivotal role in chronic inflammation;however,the molecular mechanisms underlying NAFLD/NASH from the perspective of innate immune response has not yet been fully explored.In this study,we elucidated the mechanisms of how innate im-mune response modulates NAFLD/NASH pathogenesis,and demonstrated that hepatocyte nu-clear factor-1alpha(HNF1A)was suppressed and the typeⅠIFN production pathway was activated in liver tissues of patients with NAFLD/NASH.Further experiments suggested that HNF1A negatively regulates the TBK1-IRF3 signaling pathway by promoting autophagic degra-dation of phosphorylated-TBK1,which constrains IFN production,thereby inhibiting the activa-tion of type I IFN signaling.Mechanistically,HNF1A interacts with the phagophore membrane protein LC3 through its LIR-docking sites,and mutations of LIRs(LIR2,LIR3,LIR4,and LIRs)block the HNF1A-LC3 interaction.In addition,HNF1A was identified not only as a novel autop-hagic cargo receptor but also to specifically induce K33-linked ubiquitin chains on TBK1 at Lys670,thereby resulting in autophagic degradation of TBK1.Collectively,our study illustrates the crucial function of the HNF1A-TBK1 signaling axis in NAFLD/NASH pathogenesis via cross-talk between autophagy and innate immunity.

Nanoparticle(NP)-mediated APOC1 silencing to inhibit MAPK/ERK and NF-κB pathway and suppress breast cancer growth and metastasis

Breast cancer is one of the most common malignant tumors with high mortality and poor prognosis in women.There is an urgent need to discover new therapeutic targets for breast cancer metastasis.Herein,we identified that Apolipoprotein C1(APOC1)was up-regulated in primary tumor of breast cancer patient that recurrence and metastasis by immunohistochemistry(IHC).Kaplan-Meier Plotter database showed that high levels of APOC1 in breast cancer patients were strongly associated with worse overall survival(OS)and relapse-free survival(RFS).Mechanistically,APOC1 silencing significantly inhibits MAPK/ERK kinase pathway and restrains the NF-κB to decrease the transcription of target genes related to growth and metastasis in vitro.Based on this regulatory mechanism,we developed these findings into potential therapeutic drugs,glutathione(GSH)responsive nanoparticles(NPs)were used for systemic APOC1 siRNA delivery,NPs(siAPOC1)silenced APOC1 expression,and subsequently resulted in positive anti-tumor effects in orthotopic and liver metastasis models in vivo.Taken together,GSH responsive NPmediated siAPOC1 delivery was proved to be effective in regulating growth and metastasis in multiple tumor models.These findings show that APOC1 could be a potential biomarker to predict the prognosis of breast cancer patients and NP-mediated APOC1 silencing could be new strategies for exploration of new treatments for breast cancer metastasis.

CMKLR1 senses chemerin/resolvin E1 to control adipose thermogenesis and modulate metabolic homeostasis

Induction of beige fat for thermogenesis is a potential therapy to improve homeostasis against obesity.β3-adrenoceptor(β3-AR),a type of G protein-coupled receptor(GPCR),is believed to mediate the thermogenesis of brown fat in mice.However,β3-AR has low expression in human adipose tissue,precluding its activation as a standalone clinical modality.This study aimed at identifying a potential GPCR target to induce beige fat.We found that chemerin chemokine-like receptor 1(CMKLR1),one of the novel GPCRs,mediated the development of beige fat via its two ligands,chemerin and resolvin E1(RvE1).The RvE1 levels were decreased in the obese mice,and RvE1 treatment led to a substantial improvement in obese features and augmented beige fat markers.Inversely,despite sharing the same receptor as RvE1,the chemerin levels were increased in obesogenic conditions,and chemerin treatment led to an augmented obese phenotype and a decline of beige fat markers.Moreover,RvE1 and chemerin induced or restrained the development of beige fat,respectively,via the mechanistic target of rapamycin complex 1(mTORC1)signaling pathway.We further showed that RvE1 and chemerin regulated mTORC1 signaling differentially by forming hydrogen bonds with different binding sites of CMKLR1.In conclusion,our study showed that RvE1 and chemerin affected metabolic homeostasis differentially,suggesting that selectively modulating CMKLR1 may be a potential therapeutic target for restoring metabolic homeostasis.

Cellular vesicles expressing PD-1-blocking scFv reinvigorate T cell immunity against cancer

Cancer cells aberrantly express immunosuppressive checkpoint ligands and produce certain metabolites that lead to T cell exhaustion.Immune checkpoint blockade(ICB)therapy that reinvigorates exhausted T cells have achieved impressive response in clinical cancer treatment.However,the limited clinical response rate and off-tumor toxicities restrict ICB therapy.Herein,cellular vesicles displaying anti-programmed cell death-1(PD-1)single-chain variable fragment antibody(aPD-1-scFv)were prepared to reinvigorate T cell immunity to counteract cancer.The nanovesicles displaying aPD-1-scFv(aPD-1-scFv NVs)could enhance the anti-tumor activation of T cells through PD-1 blockade.Furthermore,NVs loading the A_(2a)adenosine receptor(A_(2a)R)antagonist CPI-444 assisted T cells to antagonize adenosine,an immunosuppressive metabolite produced by cancer cells.Hence,CPI-444 loaded aPD-1-scFv NVs could intensively increase the density and activity of tumor infiltrating T cells,directly restraining tumor progress and metastasis.

Integrated Au-Nanoroded Biosensing and Regulating Platform for Photothermal Therapy of Bradyarrhythmia

Bradyarrhythmia is a kind of cardiovascular disease caused by dysregulation of cardiomyocytes,which seriously threatens human life.Currently,treatment strategies of bradyarrhythmia mainly include drug therapy,surgery,or implantable cardioverter defibrillators,but these strategies are limited by drug side effect,surgical trauma,and instability of implanted devices.Here,we developed an integrated Au-nanoroded biosensing and regulating platform to investigate the photothermal therapy of cardiac bradyarrhythmia in vitro.Au-nanoroded electrode array can simultaneously accumulate energy from the photothermal regulation and monitor the electrophsiological state to restore normal rhythm of cardiomyocytes in real time.To treat the cardiomyocytes cultured on Au-nanoroded device by near-infrared(NIR)laser irradiation,cardiomyocytes return to normal for long term after irradiation of suitable NIR energy and maintenance.Compared with the conventional strategies,the photothermal strategy is more effective and convenient to regulate the cardiomyocytes.Furthermore,mRNA sequencing shows that the differential expression genes in cardiomyocytes are significantly increased after photothermal strategy,which are involved in the regulation of the heart rate,cardiac conduction,and ion transport.This work establishes a promising integrated biosensing and regulating platform for photothermal therapy of bradyarrhythmia in vitro and provides reliable evidence of photothermal regulation on cardiomyocytes for cardiological clinical studies.