ATM Inhibition-Induced ISG15/IFI27/OASL Is Correlated with Immunotherapy Response and Inflamed Immunophenotype

Abstract

Immune checkpoint blockade (ICB) therapy can improve the survival of cancer patients with a high tumor mutation burden (TMB-H) or deficiency in DNA mismatch repair (dMMR) in their tumors. However, most cancer patients without TMB-H and dMMR do not benefit from ICB therapy. The inhibition of ATM can increase DNA damage and activate the interferon response, thus modulating the tumor immune microenvironment (TIME) and the efficacy of ICB therapy. In this study, we showed that ATM inhibition activated interferon signaling and induced interferon-stimulated genes (ISGs) in cisplatin-resistant and parent cancer cells. The ISGs induced by ATM inhibition were correlated with survival in cancer patients who received ICB therapy. In oral cancer, high expressions of ISG15, IFI27, and OASL were associated with low expressions of ATM, the activation of inflamed immune pathways, and increased tumor-infiltrating scores of CD8+ T, natural killer, and dendritic cells. The high expressions of ISG15, IFI27, and OASL were also correlated with complete remission in patients with cervical cancer treated with cisplatin. These results suggest that ATM inhibition can induce the interferon response and inflamed TIME, which may benefit ICB therapy.

Protumorigenic Interferon-Stimulated Genes in Cancer: A Comprehensive Review

“…Increase in expression of OASL in oral cancer tissue with negative association with ATM Biomarker [36] Oral squamous cell carcinoma The reports claimed that some ISGs including IFI6, IFI27 and RSAD2 showed anti-apoptotic roles by directly inhibiting the apoptosis pathway such as arresting the cell cycle leading to inhibition of apoptosis [27,50,51]. For example, IFI6 is shown to directly inhibit the TRAIL-induced extrinsic apoptotic pathway [52], whereas MX1 activates PHMG-P to indirectly block the apoptotic process [31].…”