An accurate diagnostic approach for urothelial carcinomas based on novel dual methylated DNA markers in small-volume urine

Diagnostic methods for urothelial carcinomas(UCs)are often invasive or have suboptimal accuracy.Methylation of exfoliated cell DNA or cell-free DNA in urine has shown great promise in the diagnosis of UCs.However,most current studies have focused on bladder cancer(BCa),and only a few high-plex methylated DNA panels based on large-volume urine have been reported to exhibit both high sensitivity and specificity.[1,2]The purpose of this study was to identify universal biomarkers for BCa and upper tract urothelial carcinoma(UTUC)using a small volume of urine.We developed a dual-target diagnostic panel comprising the novel marker AL021918.2 and the well-known BCa biomarker Vimentin(VIM).This panel can accurately detect UCs using only 1.8 mL of full-voided urine.

Trogocytosis of CAR molecule regulates CAR-T cell dysfunction and tumor antigen escape

Chimeric antigen receptor(CAR)T-cell therapy has demonstrated clinical response in treating both hematologic malignancies and solid tumors.Although instances of rapid tumor remissions have been observed in animal models and clinical trials,tumor relapses occur with multiple therapeutic resistance mechanisms.Furthermore,while the mechanisms underlying the long-term therapeutic resistance are well-known,short-term adaptation remains less understood.However,more views shed light on short-term adaptation and hold that it provides an opportunity window for long-term resistance.In this study,we explore a previously unreported mechanism in which tumor cells employ trogocytosis to acquire CAR molecules from CAR-T cells,a reversal of previously documented processes.This mechanism results in the depletion of CAR molecules and subsequent CAR-T cell dysfunction,also leading to short-term antigen loss and antigen masking.Such type of intercellular communication is independent of CAR downstream signaling,CAR-T cell condition,target antigen,and tumor cell type.However,it is mainly dependent on antigen density and CAR sensitivity,and is associated with tumor cell cholesterol metabolism.Partial mitigation of this trogocytosis-induced CAR molecule transfer can be achieved by adaptively administering CAR-T cells with antigen density-individualized CAR sensitivities.Together,our study reveals a dynamic process of CAR molecule transfer and refining the framework of clinical CAR-T therapy for solid tumors.