Immunotherapy based on checkpoint inhibitors provides substantial clinical benefit, but only to a minority of cancer patients. Targeted immunological checkpoint pathways have demonstrated anti-tumor cytotoxicity in the treatment of refractory cancers. However, cancer cells release specific “drones”, such as small vesicles, which increase their ability in the blood and released the proteins such as PD-L1 to block the attack from T cells then they have a change to reach the tumor forming. To characterization of exosomes forming, trafficking and secretion can be a novel therapeutic approach to improve immunotherapy in cancer patients. The ATPase H+ Transporting V0 and V1 subunits (V-ATPase, also called ATP6 family) are critical for acidifying a variety of intracellular compartments and lysosomal exocytosis. Nevertheless, the dysfunctional roles of V-ATPases in glioblastoma has not yet been elucidated. For this purposed, we investigated V-ATPase members in lysosomal vesicles and found several candidates are key factors in regulating lysosomal exocytosis in glioblastoma cells. We established transcriptomics datasets by various glioblastoma cell lines, the results showed V-ATPases are highly expressed in malignant cell lines compared to benign or normal immortalized cells. Immunohistochemistry also performed a trend of consistency that increased of V-ATPase expression in tumor parts than normal adjacent tissues. The expression level of several V-ATPase subunits is also associated with clinical parameters and survival rate. Moreover, we observed the number of tumor infiltrating lymphocyte (TILs) was decreased in clinical cohorts and two-way cell models. Therefore, we established V-ATPases related proteomics datasets and found some interaction partners could stabilized protein structure of V-ATPase. Specific peptide can compete between V-ATPase and the interacting partners and further modulate TILs in glioblastoma. This approach can be a novel therapeutic strategy that combines immunotherapy to against glioblastoma in clinical patients.

Citation Format: Yu-Chan Chang, Michael Hsiao. V-ATPase family regulates lysosomal exocytosis and neutralizes with tumor-infiltrating lymphocytes for glioblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1092.