Abstract SY09-02: A novel genetic mechanism of evading antitumor immunity in multiple human cancers

Abstract

Abstract Immune checkpoint blockade therapy using antibodies against programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-L1) is revolutionizing cancer treatment. Surprising therapeutic responses to these agents are obtained in many advanced cancer patients with different tumor types, such as melanoma, non-small-cell lung cancer, kidney cancer, and Hodgkin lymphoma, suggesting that cancer cells depend critically on evading immune surveillance for their malignant growth. Accumulating evidence suggests that these antibodies convey their therapeutic effects through targeting the PD-1/PD-L1 immune checkpoint to unleash antitumor immune responses. However, the genetic basis for the PD-1/PD-L1-mediated immune escape has not been fully elucidated, with the exception of enhanced PD-L1 expression by gene amplification and utilization of an ectopic promoter by translocation, which were reported in Hodgkin and other B-cell lymphomas as well as stomach adenocarcinoma. Only a few genetic markers are currently available to reliably predict response to anti-PD-1/PD-L1 therapy as well. I will show a unique genetic mechanism of immune escape caused by structural variations (SVs) commonly disrupting the 3′ region of the PD-L1 gene. Widely affecting multiple common human cancer types, including adult T-cell leukemia/lymphoma (27%), diffuse large B-cell lymphoma (8%), and stomach adenocarcinoma (2%), these SVs invariably lead to a marked elevation of aberrant PD-L1 transcripts that are stabilized by truncation of the 3′-untranslated region (UTR). Disruption of Pd-l1 3′-UTR in mice enables immune evasion of EG7-OVA tumor cells with elevated PD-L1 expression in vivo, which is effectively inhibited by PD-1/PD-L1 blockade, supporting the role of relevant SVs in clonal selection through immune evasion. Our findings not only unmask a novel regulatory mechanism of PD-L1 expression, but also suggest that PD-L1 3′-UTR disruption could serve as a genetic marker to identify cancers that actively evade antitumor immunity through PD-L1 overexpression. Citation Format: Seishi Ogawa. A novel genetic mechanism of evading antitumor immunity in multiple human cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY09-02. doi:10.1158/1538-7445.AM2017-SY09-02