Abstract
BackgroundTumor-reactive CD8+ tumor-infiltrating lymphocytes (TILs) represent a subtype of T cells that can recognize and destroy tumor specifically. Understanding the regulatory mechanism of tumor-reactive CD8+ T cells has important therapeutic implications. Yet the DNA methylation status of this T cell subtype has not been elucidated.ResultsIn this study, we segregate tumor-reactive and bystander CD8+ TILs, as well as naïve and effector memory CD8+ T cell subtypes as controls from colorectal cancer patients, to compare their transcriptome and methylome characteristics. Transcriptome profiling confirms previous conclusions that tumor-reactive TILs have an exhausted tissue-resident memory signature. Whole-genome methylation profiling identifies a distinct methylome pattern of tumor-reactive CD8+ T cells, with tumor-reactive markers CD39 and CD103 being specifically demethylated. In addition, dynamic changes are observed during the transition of naïve T cells into tumor-reactive CD8+ T cells. Transcription factor binding motif enrichment analysis identifies several immune-related transcription factors, including three exhaustion-related genes (NR4A1, BATF, and EGR2) and VDR, which potentially play an important regulatory role in tumor-reactive CD8+ T cells.ConclusionOur study supports the involvement of DNA methylation in shaping tumor-reactive and bystander CD8+ TILs, and provides a valuable resource for the development of novel DNA methylation markers and future therapeutics.
Highlights
Tumor-reactive CD8+ tumor-infiltrating lymphocytes (TILs) represent a subtype of T cells that can recognize and destroy tumor
Recent literatures reported that the thymocyte selection-associated high mobility group box (TOX) protein is required for the development and maintenance of exhausted T cell populations in chronic infection [15,16,17,18]
Our previous single-cell RNA-sequencing data identified the specific expression of TOX in exhausted CD8+ TILs [19,20,21] (Additional file 1: Figure S2B-D)
Summary
Tumor-reactive CD8+ tumor-infiltrating lymphocytes (TILs) represent a subtype of T cells that can recognize and destroy tumor . Co-expression of CD39 (ENTPD1) and CD103 (ITGAE) identifies such a unique T cell population [1, 3]. These cells have a tissueresident memory (RM) signature with high expression of exhaustion markers, such as PDCD1 and HAVCR2 ( known as Tim-3). These TILs exhibited low expression of CCR7, CD127, and CD28, indicative of an effector memory (EM) phenotype [3, 5]. Further investigation is needed to better distinguish the molecular natures of TEM and this tumor-reactive T cell subtype
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