Abstract LB-118: A conserved checkpoint molecule signature offers novel targets for tumor specific regulatory T cell manipulation

Abstract

Abstract Regulatory T (Treg) cells play an important role in modulating the tumor microenvironment, leading to the suppression of anti-tumor immune responses. Tumor Tregs could be targeted by taking advantage of the differential expression of immune checkpoints on these cells as compared to other T cell subsets. While the elevated expression of checkpoints such as CTLA-4 on Tregs compared to conventional T cells is well-characterized, less is known about the collective landscape of Treg specific checkpoint expression specific in the tumor microenvironment. We identified a network of Treg-associated checkpoint markers including those previously associated with Treg function (CTLA4, ICOS) as well as several additional checkpoints (BTLA, LAG3, TIGIT, TNFRSF9) by characterizing the expression of 28 checkpoint molecules across 7,608 bulk tumor samples (31 tumor types) from TCGA. We then utilized whole transcriptome RNA sequencing of purified peripheral and tumor Treg cell populations across 4 different tumor types (glioblastoma multiforme, prostatic adenocarcinoma, urothelial transitional cell carcinoma, renal clear cell carcinoma) to characterize the Treg specific expression of checkpoint molecules. Peripheral and tumor Tregs demonstrate differential checkpoint expression landscapes, with tumor Tregs uniquely discriminated by collective expression of TNFRSF9 (4-1BB), HAVCR-2 (TIM-3), and LAG-3. This discriminatory signature was conserved across the 4 profiled tumor types, was associated with changes in Treg biology, and was confirmed in published data from three additional cancer cohorts (breast, colorectal, and non-small-cell-lung cancers). Furthermore, normalized TNFRSF9 expression in TCGA was also associated with a worse survival outcome, suggesting that elevated Treg TNFRSF9 expression may be a poor prognostic factor across a wide range of tumors. Taken together, these data highlight the potential of targeting TNFRSF9 expressing Tregs in the tumor as a novel immunotherapeutic approach for several types of cancer. Citation Format: Zachary T. Freeman, Daniel H. Hovleson, Alexander T. Pearson, Jingyi Zhai, Ali Ghasemzadeh, Thomas R. Nirschl, Hui Jiang, Scott A. Tomlins, Charles G. Drake. A conserved checkpoint molecule signature offers novel targets for tumor specific regulatory T cell manipulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-118.