Mellman, I. | bioRxiv Science

bioRxiv2018

Transposable Element Expression In Tumors Is Associated With Immune Infiltration And Increased Antigenicity

Profound loss of DNA methylation is a well-recognized hallmark of cancer. Given its role in silencing transposable elements (TEs), we hypothesized that extensive TE expression occurs in tumors with highly demethylated DNA. We developed REdiscoverTE, a computational method for quantifying genome-wide TE expression in RNA sequencing data. Using The Cancer Genome Atlas database, we observed increased expression of over 400 TE subfamilies, of which 262 appeared to result from a proximal loss of DNA methylation. The most recurrent TEs were among the evolutionarily youngest in the genome, predominantly expressed from intergenic loci, and associated with antiviral or DNA damage responses. Treatment of glioblastoma cells with a demethylation agent resulted in both increased TE expression and de novo presentation of TE-derived peptides on MHC class I molecules. Therapeutic reactivation of tumor-specific TEs may synergize with immunotherapy by inducing both inflammation and the display of potentially immunogenic neoantigens.\n\nOne Sentence SummaryTransposable element expression in tumors is associated with increased immune response and provides tumor-associated antigens

cancer biology↗

bioRxiv2016

T cell co-stimulatory receptor CD28 is a primary target for PD-1-mediated inhibition

Programmed death-1 (PD-1) is a co-inhibitory receptor that suppresses T cell activation and is an important cancer immunotherapy target. Upon activation by its ligand PD-L1, PD-1 is thought to suppress signaling through the T cell receptor (TCR). Here, by titrating the strength of PD-1 signaling in both biochemical reconstitution systems and in T cells, we demonstrate that the coreceptor CD28 is strongly preferred over the TCR as a target for dephosphorylation by PD-1- recruited Shp2 phosphatase. We also show that PD-1 colocalizes with the costimulatory receptor CD28 in plasma membrane microclusters but partially segregates from the TCR. These results reveal that PD-1 suppresses T cell function primarily by inactivating CD28 signaling, suggesting that costimulatory pathways may play unexpected roles in regulating effector T cell function and therapeutic responses to anti-PD-L1/PD-1.

biochemistry↗