摘要
Objectives:Gastric-type adenocarcinoma(GAS),an aggressive subtype of non-human papillomavirus(HPV)-associated(NH-PVA)cervical adenocarcinomas(ADC),remains a treatment-refractory disease with poor prognosis.This study aims to explore the oncogenic mechanism and efficacious therapeutic target of GAS.Methods:We included 19 NHPVA and 153 HPVA ADC patients from our center to investigate clinicopathological features.We collected 3 GAS and 2 usual-type endocervical adenocarcinomas(UEA)for single-cell RNA sequencing and T-cell receptor se-quencing.We conducted immunohistochemical staining of 25 GAS and 25 UEA samples and multicolor immunohistochemical staining of 2 GAS samples for validation.We explored the efficacy of anti-clusterin(OGX-011)and/or cisplatin(DDP)for GAS based on GAS-derived tumoroids.Results:Based on clinical data,we clinicopathologically verified the malignancy of GAS.Through single-cell RNA sequencing,we delineated key cell subtypes including GAS epithelial cells,“GAS-enriched fibroblasts”,“GAS-associatedγδT cells”,and CD8+exhausted T cells enduring heat stress and contributing to GAS aggressive phenotype.Regarding validation,we verified clusterin(CLU)-associated heat stress,highlighted the potential role of CLU-associated stress in promoting immune escape,and established a four-gene signature(CLU,PDGFB,TIGIT,and C3)indicating poor prognosis of GAS induced by CLU-associated stress and immune escape.Based on GAS-derived tumoroids retaining the histological features,CLU-associated stress,and genetic profile of parental tumor,we validated the anti-tumor and sensitizing DDP efficacy of targeting CLU.Conclusion:CLU-associated heat stress of key cell subtypes contributed to the malignant GAS microenvironment.Additionally,we pioneeringly constructed GAS-derived tumoroids and suggested that combining CLU-targeted treatment and DDP could improve the therapeutic efficacy for GAS.
基金
supported by funding from Medical Innova-tion Research of Shanghai Science and Technology(grant No.22Y31900500 to K.H.and grant No.21Y11906900 to J.Q.)
National Natural Science Foundation of China(grant No.82173188 to K.H.and grant No.82472993 to J.Q.)
Shanghai Municipal Hospital De-velopment Center(grant No.SHDC22021307 to K.H.)
Shang-hai Municipal Health Commission(grant No.202040498 to J.Q.)。
