Chemokine Ligand 13 Expression is Abundant in the Tumor Microenvironment and Indicates Poor Prognosis of Kidney Clear Cell Carcinoma

The chemokine ligand 13-chemokine receptor 5(CXCL13-CXCR5)axis has been characterized as a critical tumor-promoting signaling pathway in the tumor microenvironment(TME)in multiple types of solid tumors.In this study,we analyzed the expression profile of CXCL13 in kidney clear cell carcinoma(KIRC)and its correlation with tumor-infiltrating immune cells(TIICs).A monoclonal antibody against CXCL13 with high affinity and purity was generated in our lab for western blot and immunohistochemistry(IHC).Bioinformatic analysis was performed based on bulk-seq data from the Cancer Genome Atlas(TCGA)-KIRC and single-cell RNA-seq data from scRNASeqDB and PanglaoDB.Results showed that high CXCL13 expression in TME was associated with shorter progression-free survival(PFS),disease-specific survival(DSS),and overall survival(OS).KIRC cell lines,as well as several other cancer cell lines,had negative CXCL13 expression.IHC staining from the Human Protein Atlas(HPA)and our tissue array indicated that CXCL13 might be mainly expressed by TIICs,but not KIRC tumor cells.CXCL13 expression was strongly and positively correlated withγδT cell abundance in TME.Besides,γδT cell infiltration was associated with poor survival of KIRC.Methylation 450k array data showed that CXCL13 promoter hypomethylation was common in TIICs.The methylation level of cg16361705 within the CXCL13 promoter might play an important role in modulating CXCL13 transcription.In conclusion,our study revealed that CXCL13 expression andγδT cell infiltration in TME is associated with unfavorable survival of KIRC.TIICs,most possiblyγδT cells,are the dominant source of CXCL13 in KIRC TME.

Antibody-drug conjugates:Recent advances in payloads

Antibody-drug conjugates(ADCs),which combine the advantages of monoclonal antibodies with precise targeting and payloads with efficient killing,show great clinical therapeutic value.The ADCs’payloads play a key role in determining the efficacy of ADC drugs and thus have attracted great attention in the field.An ideal ADC payload should possess sufficient toxicity,low immunogenicity,high stability,and modifiable functional groups.Common ADC payloads include tubulin inhibitors and DNA damaging agents,with tubulin inhibitors accounting for more than half of the ADC drugs in clinical development.However,due to clinical limitations of traditional ADC payloads,such as inadequate efficacy and the development of acquired drug resistance,novel highly efficient payloads with diverse targets and reduced side effects are being developed.This perspective summarizes the recent research advances of traditional and novel ADC payloads with main focuses on the structure-activity relationship studies,co-crystal structures,and designing strategies,and further discusses the future research directions of ADC payloads.This review also aims to provide valuable references and future directions for the development of novel ADC payloads that will have high efficacy,low toxicity,adequate stability,and abilities to overcome drug resistance.

Therapeutic potential of an anti-HER2 single chain antibody-DM1 conjugates for the treatment of HER2-positive cancer

Antibody–drug conjugates(ADCs)take the advantage of monoclonal antibodies to selectively deliver highly potent cytotoxic drugs to tumor cells,which have become a powerful measure for cancer treatment in recent years.To develop a more effective therapy for human epidermal growth factor receptor 2(HER2)-positive cancer,we explored a novel ADCs composed of anti-HER2 scFv–HSA fusion antibodies conjugates with a potent cytotoxic drug DM1.The resulting ADCs,T-SA1–DM1 and T-SA2–DM1(drug-to-antibody ratio in the range of 3.2–3.5)displayed efficient inhibition in the growth of HER2-positive tumor cell lines and the half-maximal inhibitory concentration on SKBR-3 and SKOV3 cells were both at the nanomolar levels in vitro.In HER2-positive human ovarian cancer xenograft models,T-SA1–DM1 and T-SA2–DM1 also showed remarkable antitumor activity.Importantly,three out of six mice exhibited complete remission without regrowth in the high-dose group of T-SA1–DM1.On the basis of the analysis of luminescence imaging,anti-HER2 scFv–HSA fusion antibodies,especially T-SA1,showed strong and rapid tumor tissue penetrability and distribution compared with trastuzumab.Collectively,the novel type of ADCs is effective and selective targeting to HER2-positive cancer,and may be a promising antitumor drug candidate for further studies.