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Targeting the aminopeptidase ERAP enhances antitumor immunity by disrupting the NKG2A-HLA-E inhibitory checkpoint
Hsiao-Wei Tsao, et al.
Immunity. 2024
In this study, they demonstrate that the loss of ERAP1 in tumors enhances the effectiveness of immune checkpoint blockade (ICB) by disrupting the HLA-E/Qa-1b-NKG2A inhibitory pathway. They discovered that ERAP is essential for trimming N-terminal peptides necessary for HLA-E/Qa-1b presentation, and without ERAP, these peptides cannot be generated or loaded. Consequently, the NKG2A/CD94 inhibitory receptor fails to bind to HLA-E/Qa-1b, leading to reduced NKG2A-mediated inhibition and increased cytotoxic activity from CD8+ T cells and NK cells. This suggests that the absence of ERAP mimics the loss of HLA-E/Qa-1b or NKG2A, indicating that inhibiting ERAP's enzymatic function can deactivate this critical checkpoint. While their findings highlight that ERAP deletion enhances immunotherapy sensitivity by disrupting the HLA-E checkpoint, they also recognize potential additional immune-sensitizing effects due to changes in the classical MHC class I peptidome. Their peptidomic analysis confirmed that ERAP loss significantly alters this peptidome, including longer peptide presentations, which can be immunogenic. Notably, immunization with ERAP-deficient splenocytes in wild-type mice elicits strong T cell responses. Furthermore, they observed that ERAP deletion in tumor cells increases the presentation of atypical peptides on HLA-E/Qa-1b, which may be recognized by CD8+ T cells. This could lead to novel antigen presentations on HLA-E/Qa-1b and merits further investigation. Importantly, species differences between mice and humans must be considered since humans possess both ERAP1 and ERAP2 genes. Their results indicate that in most human cancer cells, both ERAP1 and ERAP2 need to be inhibited to eliminate VL9 presentation by HLA-E. Overall, this research positions ERAP1/2 as vital targets for enhancing ICB efficacy in cancer immunotherapy.
DOI: 10.1016/j.immuni.2024.10.013
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Siyu Sun, et al.
Immunity. 2024
To survive, cancer cells must navigate the balance between their oncogenic potential and the immunogenic costs associated with it. Their findings reveal that various types of retrotransposons can have both pro- and anti-tumor effects. Specifically, immunostimulatory SINEs, particularly from the AluY and AluS families, appear to promote anti-tumor activity through RIG-I-like receptors (such as MDA5), which activate interferon gene pathways. However, "viral mimicry" induced by double-stranded RNA from IRAlus can be harmful to tumors and needs to be suppressed. They propose that a critical adaptive mechanism for cancer cells involves managing immunostimulatory Alus, as evidenced by convergent evolutionary strategies across different genetic contexts. One such strategy involves L1 activity, especially in tumors with mutant TP53, which suppresses Alu activity and enhances immune evasion. In tumors where TP53 is compromised, new L1 insertions frequently occur. Conversely, tumors with wild-type TP53 tend to utilize ADAR1-mediated RNA editing to neutralize Alu dsRNA. Their model suggests that tumors regulate dsRNA viral mimics by altering their levels through L1 repression and ADAR1 editing based on TP53 status. They developed a predictive mathematical model simulating RLR-IFN signaling influenced by ADAR1 and L1 contributions. Interestingly, their simulations align closely with the prevalence of TP53 mutations in pancreatic ductal adenocarcinoma (PDAC). In advanced tumors, they observed a correlation between increased L1 activity and a shift from anti- to pro-tumor signaling. This remodeling appears to occur later in tumor progression, as indicated by decreased CD8+ cell infiltration alongside high ORF1p levels. Overall, their study highlights the complex interplay of retrotransposons in cancer biology and suggests that understanding these dynamics may lead to precision therapies tailored to specific tumor genetic contexts.
DOI: 10.1016/j.immuni.2024.10.015
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