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Reactive CD8+ T Cells in Colorectal Cancer Patients Revealed By Yang et al. Genome Biology (2020) 21:2 https://doi.org/10.1186/s13059-019-1921-y RESEARCH Open Access Distinct epigenetic features of tumor- reactive CD8+ T cells in colorectal cancer patients revealed by genome-wide DNA methylation analysis Rui Yang1†, Sijin Cheng1†, Nan Luo2,3†, Ranran Gao1, Kezhuo Yu4, Boxi Kang1, Li Wang1, Qiming Zhang1, Qiao Fang4, Lei Zhang4, Chen Li5, Aibin He5, Xueda Hu1, Jirun Peng2,3*, Xianwen Ren1* and Zemin Zhang1,4* Abstract Background: Tumor-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. Results: In 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. Conclusion: Our 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. Keywords: Colorectal cancer, Tumor-reactive T cells, Bystanders, Transcriptome, Methylome, Transcription factor, T cell exhaustion Background development. CRC treatment usually involves surgical Colorectal cancer (CRC) is one of the most common removal of the tumor followed by adjuvant chemother- cancers globally. CRC incidence has traditionally been apy. In recent years, various kinds of immunotherapies, the highest in affluent western countries, but it is now such as checkpoint blockade immunotherapy, have been increasing rapidly in other countries with economic used to enhance the antitumor potential. However, the responses to these treatments vary among patients. Re- cent literatures supported the notion that not all tumor- * Correspondence: [email protected]; [email protected]; – [email protected] infiltrating lymphocytes (TILs) are tumor reactive [1 4]. †Rui Yang, Sijin Cheng and Nan Luo contributed equally to this work. Rather, bystander cells exist, which recognize a wide 2 Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, range of epitopes unrelated to cancer [1–4]. For tumor Beijing, China 1BIOPIC, Beijing Advanced Innovation Center for Genomics, and School of immunotherapy, it is valuable to target those cells of Life Sciences, Peking University, Beijing, China which the T cell receptor (TCR) repertoire is Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Yang et al. Genome Biology (2020) 21:2 Page 2 of 13 intrinsically tumor reactive. Co-expression of CD39 bystanders [1, 3]. To further characterize the transcrip- (ENTPD1) and CD103 (ITGAE) identifies such a unique tional profiles of these cell populations, we isolated T cell population [1, 3]. These cells have a tissue- naïve, TEM, CD103+CD39+, CD103+CD39−, and CD103 resident memory (RM) signature with high expression of −CD39− T cell subtypes from eight CRC patients for exhaustion markers, such as PDCD1 and HAVCR2 (also gene expression profiling using adapted Smart-seq II known as Tim-3). Interestingly, these TILs also exhibited (Fig. 1a–c; Additional file 1: Figure S1A, B; the low expression of CCR7, CD127,andCD28, indicative of “Methods” section). As shown in the heat map display- an effector memory (EM) phenotype [3, 5]. Understand- ing differentially expressed genes (DEGs) among five ing the molecular basis of memory CD8+ T cells is key CD8+ T cell subtypes, the naïve subtype exhibited high to developing effective therapies against cancers. Further expression of known naïve markers LEF1 and SELL (also investigation is needed to better distinguish the molecu- known as CD62L) (Fig. 1d; Additional file 1: Figure lar natures of TEM and this tumor-reactive T cell S1C). TEM subtype showed enhanced expression of clas- subtype. sically defined TEM molecules, such as TBX21 [13] and Gene expression patterns, a key determinant for a cel- CX3CR1 [14] (Fig. 1d). Notably, CD103+CD39+ TILs lular feature, are believed to be controlled by epigenetic displayed hallmarks of an “exhausted” phenotype, with changes [6]. Decoding the epigenome specific to tumor- high expression of CTLA4, HAVCR2, and LAYN (Fig. 1d; reactive T cells is a pivotal step toward understanding Additional file 1: Figure S1C, D). Recent literatures re- the activation and expansion of this T cell population in ported that the thymocyte selection-associated high mo- cancer. However, how they are regulated epigenetically bility group box (TOX) protein is required for the has not been addressed thus far. DNA methylation, a co- development and maintenance of exhausted T cell popu- valent modification of the DNA molecule, is a stable and lations in chronic infection [15–18]. Removal of its DNA heritable form of epigenetic modifications which partici- binding domain reduced the expression of PD-1 and re- pates in establishing and maintaining chromatin struc- sulted in a more polyfunctional T cell phenotype [16]. tures and regulates gene transcription [7]. In general, Here, we observed that TOX expression is also upregu- DNA methylation is critical for establishing stable gene- lated (Fig. 1d; Additional file 1: Figure S2A). Intriguingly, silencing programs, by affecting the interactions of DNA our previous single-cell RNA-sequencing (scRNA-seq) with chromatin proteins and transcription factors [8, 9]. data identified the specific expression of TOX in Many studies have highlighted the importance of DNA exhausted CD8+ TILs [19–21] (Additional file 1: Figure methylation in regulating complex gene expression pro- S2B-D). These data together supported the important grams underlying immune responses [10–12]. It is thus role of TOX in intratumoral T cell exhaustion. important to define how the identities of tumor-reactive Gene set variation analysis (GSVA) showed that CD8+ T cells and bystanders are shaped at methylation CD103+CD39+ subtype was enriched in biological pro- level, including particular genes and networks. cesses associated with immunomodulation, such as In this study, we sorted tumor-reactive and bystander “regulation of interferon gamma biosynthesis” and CD8+ TILs from treatment-naïve primary CRC patients “negative regulation of IL10 production” [22, 23] based on the expression of CD39 and CD103, and naïve (Fig. 1e). Furthermore, we analyzed effector function of and TEM CD8+ T cells from peripheral blood based on these CD8 T cell subtypes by the expression of gran- the expression of CD45RO, CD45RA, and CCR7. zyme A/B/H, cytotoxic granules PRF1, interferon (IFN)- Adapted smart-seq2 and whole-genome bisulfite sequen- γ, and tumor necrosis factor (TNF). Interestingly, we cing (bisulfite-seq) were performed to characterize the found that exhausted CD103+CD39+ subtype still had transcriptomic features, DNA methylome programming, relatively high expression of these cytotoxic proteins methylation dynamics, and key transcription factors (Additional file 1: Figure S1C). Together with the GSVA (TFs) in each T cell subtype. Our study can help under- results, it indicates that CD103+CD39+ subtype may not stand the underlying mechanisms leading to the specific have lost their antitumor potential. Two-dimensional expression patterns of tumor-reactive CD8+ T cells, principal component analysis (PCA) revealed that naïve thereby facilitating the development of new therapeutic and TEM subtypes were clearly grouped as distinct popu- strategies targeting these cells. lations, whereas three CD8+ TIL subtypes appeared tightly clustered, indicative of a very similar transcrip- Results tional profile among these subtypes (Fig. 1f). Transcriptomic characteristics of five CD8+ T cell To gain a deeper understanding of tumor-reactive subtypes CD8+ T cells, we compared them with their counterpart, Within CD8+ TILs, CD103+CD39+ T cells have been CD103−CD39− cells. CD103+CD39+ T cells highly recently demonstrated to be tumor-reactive, while expressed a set of 435 genes, including T cell exhaustion CD103−CD39− T cells and CD103+CD39− T cells are markers
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