On Monday 3rd April at AACR 2017, during the “SY16 - Mechanisms Regulating Immune Checkpoint Therapies” session, Seishi Ogawa of Kyoto University Graduate School of Medicine, Kyoto-shi Sakyo-ku, Japan, gave a talk titled “A novel genetic mechanism of evading antitumor immunity in multiple human cancers.”
The talk began by explaining that tumor cells utilize PD-L1 signaling to escape from the host’s immune response; immunotherapy resulting in PD-L1 blockade prevents this occurring.
Antibodies against PD-1/PD-L1 include nivolumab and pembrolizumab and can be used against a variety of cancer types including lung, kidney, ovarian, colorectal, and head & neck cancers, as well as melanoma and Hodgkin Lymphoma. In those that do respond, anti-PD-1/PD-L1 antibodies achieve durable responses. However, ORR is only around 20–30% and super responders are rare (1–2%). Organ damage (sometimes life-threatening) can occur because of auto-immunity and there are currently no reliable markers for predicting response.
Seishi Ogawa then focused the talk of Adult T-Cell Leukemia/Lymphoma (ATL):
There is a long latency period before the onset of ATL. Infection with HTLV-1 is not enough to develop ATL; genetic alterations in cellular and/or viral genes are required.
During genetic analysis of ATL samples, a novel breakpoint cluster was identified at the PD-L1 locus (9p24.1). This area is affected by a range of Structural Variants (SVs) which often result in the 3’ UTR being disrupted; often truncating the 3’ UTR. In SV+ ATL samples, PD-L1 expression has been found to be increased.
Moreover, surface expression and PD-1 binding ability is preserved in aberrantly expressed PD-L1, and experiments disrupting the 3’ UTR resulted in stabilization of PD-L1 transcripts.
In other cancers, such as Lung Adenocarcinoma and Skin Squamous Cell Cancer, as PD-L1 expression increases, anti-tumor response (cytolytic activity) decreases.
Moreover, Ogawa presented data of a mouse SV+ thymoma model which demonstrated that cancer cells escape the immune response, however administration of αPd-l1 antibody disrupts immune evasion resulting in a decrease in tumor volume. Other slides were also presented, showing data that disruption of PD-L2 3’ UTR also increases PD-L2 expression.
The talk was concluded with a succinct summary slide, and Ogawa emphasized the unexpected role of 3’ UTR regulation in expression of PD-L1 and PD-L2. Screening for SVs involving 3’ UTRs could potentially identify patients whose cancers actively evade their immune response, and could become a novel marker for predicting patients’ responses to therapy using immune checkpoint blockade.