Biology subjects

Peretz, T.

Publications and source records attributed to Peretz, T..

3 recordsLinked to original sources

bioRxiv2021

Multiplexed Single-Molecule Epigenetic Analysis of Plasma-Isolated Nucleosomes for Cancer Diagnostics

The analysis of cell-free DNA (cfDNA) in plasma represents a rapidly advancing field in medicine, providing information on pathological processes in the body. Blood cfDNA is in the form of nucleosomes, which maintain their tissue- and cancer-specific epigenetic state. We developed EPINUC, a single-molecule multi-parametric assay to comprehensively profile the Epigenetics of Plasma Isolated Nucleosomes, DNA methylation and cancer-specific protein biomarkers. Our system allows high-resolution detection of six active and repressive histone modifications, their ratios and combinatorial patterns, on millions of individual nucleosomes by single-molecule imaging. In addition, it provides sensitive and quantitative data on plasma proteins, including detection of non-secreted tumor-specific proteins such as mutant p53. Applying this analysis to a cohort of plasma samples detected colorectal cancer at high accuracy and sensitivity, even at early stages. Finally, combining EPINUC with direct single-molecule DNA sequencing revealed the tissue-of-origin of colorectal, pancreatic, lung and breast tumors. EPINUC provides multi-layered clinical-relevant information from limited liquid biopsy material, establishing a novel approach for cancer diagnostics.

cancer biology↗

bioRxiv2020

Alternative splicing of SLAMF6 in human T cells creates a co-stimulatory isoform that counteracts the inhibitory effect of the full-length receptor

SLAMF6 is a homotypic receptor of the Ig-superfamily associated with progenitor exhausted T cells. In humans, SLAMF6 has three splice isoforms involving its V-domain. While the canonical 8-exon receptor inhibits T cell activation through SAP recruitment, the short isoform SLAMF6{Delta}17-65 has a strong agonistic effect. The costimulatory action depends on protein phosphatase SHP-1 and leads to a cytotoxic molecular profile governed by transcription factors Tbet, Runx3, and Tcf7. In T cells from individual patients treated with immune checkpoint blockade, a shift was noted towards SLAMF6{Delta}17-65. Splice-switching antisense oligonucleotides designed to target the SLAMF6 splice junction, enhanced SLAMF6{Delta}17-65 in human tumor-infiltrating lymphocytes and improved their capacity to inhibit human melanoma in mice. The possible emergence of two opposing isoforms from the SLAMF6 gene may represent an immune-modulatory mechanism that can be exploited for cancer immunotherapy.

immunology↗

bioRxiv2019

SLAMF6 deficiency augments tumor killing and skews towards an effector phenotype revealing it as a new T cell checkpoint

SLAMF6 is a homotypic receptor of the Ig-superfamily whose exact role in immune modulation has remained elusive. Its constitutive expression on resting and activated T cells precludes it from being a bona fide exhaustion marker. By breeding Pmel-1 mice with SLAMF6 KO mice, we generated donors for T cells lacking SLAMF6 and expressing a transgenic TCR for gp100-melanoma antigen. Activated Pmel-1xSLAMF6 KO CD8 T cells displayed improved polyfunctionality and strong tumor cytolysis. T-bet was the dominant transcription factor in Pmel-1xSLAMF6 KO cells, and upon activation, they acquired an effector-memory phenotype. Blocking LAG-3 improved the function of SLAMF6 deficient T cells even further. Finally, adoptive transfer of Pmel-1xSLAMF6 KO T cells into melanoma-bearing mice resulted in lasting tumor regression in contrast to temporary responses achieved with Pmel-1 T cells. These results support the notion that SLAMF6 is an inhibitory immune receptor whose absence enables powerful CD8 T cells to eradicate tumors.

physiology↗