Upregulation of Apolipoprotein L6 Improves Tumor Immunotherapy by Inducing Immunogenic Cell Death

Abstract

In the past few years, immune checkpoint blockade (ICB) therapy has emerged as a breakthrough treatment for cancers and has demonstrated inspiring effects in tumor patients with Epstein-Barr virus (EBV) infection. To allow more patients to benefit from immunotherapy, exploring novel biomarkers based on EBV-related tumors and immunotherapy cohorts was pursued in the present study. The essential biomarkers that may enhance antitumor immunity across EBV-related tumors were identified using the large-scale transcriptomic profiles of EBV-associated tumors and tumor immunotherapy cohorts. The clinical significance of vital genes was evaluated in multiple tumor immunotherapy cohorts. Moreover, the potential function of essential genes in immunotherapy was explored via bioinformatic analyses and verified by qRT-PCR, Western blot analysis, CCK8 assay and flow cytometry. Apolipoprotein L6 (APOL6) was considered the essential biomarker for enhancing antitumor immunity across EBV-positive tumors. The upregulation of APOL6 was correlated with increased response rates and prolonged survival in multiple tumor immunotherapy cohorts. Bioinformatic analyses suggested that APOL6 may enhance tumor immunotherapy by inducing immunogenic cell death. Pancreatic cancer cells transfected with APOL6 overexpression plasmid underwent apoptosis, necroptosis, and pyroptosis with immunogenic features. The biomarker upregulated in EBV-related tumors could further elucidate the drivers of immunotherapy response. The upregulation of APOL6 could improve immunotherapy by triggering immunogenic cell death, thus offering a new target to optimize cancer immunotherapy.

CAR memory–like NK cells targeting the membrane proximal domain of mesothelin demonstrate promising activity in ovarian cancer

“…3, C to E). The up-regulated genes in SKOV3 after exposure to CIML NK cells could be attributed to treatment resistance and dysfunction of immune cells ( ATF4 , SLC3A2 , CARS1 , YARS1 , and MUC16 ) ( 41 – 43 ), whereas very few IFN response genes were up-regulated ( IRF9 and APOL6 ) ( 44 ) in the SKOV3 cell line (compared to the other cell lines tested). Among the up-regulated genes, we found several genes in common with the ferroptosis-related gene group ( CARS1 and CHAC1 ) ( 45 , 46 ), indicating that the ferroptosis pathway may contribute to resistance to the CIML NK cells in this cell line.…”

Intratumor APOL3 delineates a distinctive immunogenic ferroptosis subset with prognosis prediction in colorectal cancer

“…Ferroptosis is a form of regulated cell death that is morphologically, genetically, and biochemically distinct from apoptosis and necroptosis, and its potential use in anticancer therapy is emerging 40 . Apolipoproteins are a functional family of proteins involved in the movement of lipids in the cytoplasm 41 . As an apolipoprotein, APOL3 was reported in many cell types, such as endothelial cells, 25 podocyte, 42 neurones, 43 and trypanosomes 44 .…”

“… 40 Apolipoproteins are a functional family of proteins involved in the movement of lipids in the cytoplasm. 41 As an apolipoprotein, APOL3 was reported in many cell types, such as endothelial cells, 25 podocyte, 42 neurones, 43 and trypanosomes. 44 Recently, Gaudet et al.…”

“…40 Apolipoproteins are a functional family of proteins involved in the movement of lipids in the cytoplasm. 41 As an apolipoprotein, APOL3…”

Investigating the prognostic value of mTORC1 signaling in bladder cancer via bioinformatics evaluation

“…Among these genes, EMP1, AKR1B15, and IGF2 were associated with high risk, while SP6, MTATP8P1, and APOL6 were associated with low risk. EMP1 34 and IGF2 35 have been found to promote tumor growth and metastasis, while APOL6 has been found to inhibit the migration and invasion of cancer cells 36 . However, there is currently no research on the role of AKR1B15, MTATP8P1, and SP6 in cancer.…”