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Global Pattern of CD8⁺ T-Cell Infiltration and Exhaustion in Colorectal Cancer Predicts Cancer Immunotherapy Response.

ABSTRACT: Background: The MSI/MSS status does not fully explain cancer immunotherapy response in colorectal cancer. Thus, we developed a colorectal cancer-specific method that predicts cancer immunotherapy response. Methods: We used gene expression data of 454 samples (MSI = 131, MSI-L = 23, MSS = 284, and Unknown = 16) and developed a TMEPRE method that models signatures of CD8+ T-cell infiltration and CD8⁺ T-cell exhaustion states in the tumor microenvironment of colorectal cancer. TMEPRE model was validated on three RNAseq datasets of melanoma patients who received pembrolizumab or nivolumab and one RNAseq dataset of purified CD8⁺ T cells in different exhaustion states. Results: TMEPRE showed predictive power in three datasets of anti-PD1-treated patients (p = 0.056, 0.115, 0.003). CD8⁺ T-cell exhaustion component of TMEPRE model correlates with anti-PD1 responding progenitor exhausted CD8⁺ T cells in both tumor and viral infection (p = 0.048, 0.001). The global pattern of TMEPRE on 454 colorectal cancer samples indicated that 10.6% of MSS patients and 67.2% of MSI patients show biological characteristics that can potentially benefit from anti-PD1 treatment. Within MSI nonresponders, approximately 50% showed insufficient tumor-infiltrating CD8⁺ T cells and 50% showed terminal exhaustion of CD8⁺ T cells. These terminally exhausted CD8⁺ T cells coexisted with signatures of myeloid-derived suppressor cells in colorectal cancer. Conclusion: TMEPRE is a colorectal cancer-specific method. It captures characteristics of CD8⁺ T-cell infiltration and CD8⁺ T-cell exhaustion state and predicts cancer immunotherapy response. A subset of MSS patients could potentially benefit from anti-PD1 treatment. Anti-PD1 resistance MSI patients with insufficient infiltration of CD8⁺ T cells or terminal exhaustion of CD8⁺ T cells need different treatment strategies.

SUBMITTER: Tian S

PROVIDER: S-EPMC8477790 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundColorectal cancer (CRC) ranks among the most prevalent malignancies affecting the gastrointestinal tract. The infiltration of CD8+ T cells significantly influences the prognosis and progression of tumor patients.MethodsThis study establishes a CRC immune risk model based on CD8+ T cell-related genes. CD8+ T cell-related genes were identified through Weighted Gene Co-expression Network Analysis (WGCNA), and the enriched gene sets were annotated via Gene Ontology (GO) and Reactome pathway analysis. Employing machine learning methods, including the Least Absolute Shrinkage and Selection Operator (LASSO) algorithm and Random Forest (RF), we identified nine genes associated with CD8+ T-cell infiltration. The infiltration levels of immune cells in CRC tissues were assessed using the ssGSEA algorithm.ResultsThese genes provide a foundation for constructing a prognostic model. The TCGA-CRC sample model's prediction scores were categorized, and the prediction models were validated through Cox regression analysis and Kaplan-Meier curve analysis. Notably, although CRC tissues with higher risk scores exhibited elevated levels of CD8+ T-cell infiltration, they also demonstrated heightened expression of immune checkpoint genes. Furthermore, comparison of microsatellite instability (MSI) and gene mutations across the immune subgroups revealed notable gene variations, particularly with APC, TP53, and TNNT1 showing higher mutation frequencies. Finally, the predictive model's efficacy was corroborated through the use of Tumor Immune Dysfunction and Exclusion (TIDE), Immune Profiling Score (IPS), and immune escape-related molecular markers. The predictive model was validated through an external cohort of CRC and the Bladder Cancer Immunotherapy Cohort. CLRN3 expression levels in tumor and adjacent normal tissues were assessed using quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Subsequent in vitro and in vivo experiments demonstrated that CLRN3 knockdown significantly attenuated the malignant biological behavior of CRC cells, while overexpression had the opposite effect.ConclusionsThis study presents a novel prognostic model for CRC, providing a framework for enhancing the survival rates of CRC patients by targeting CD8+ T-cell infiltration.

Project description:BACKGROUND AND AIMS: Reliable prognostic markers based on biopsy specimens of colorectal cancer (CRC) are currently missing. We hypothesize that assessment of T-cell infiltration in biopsies of CRC may predict patient survival and TNM-stage before surgery. METHODS: Pre-operative biopsies and matched resection specimens from 130 CRC patients treated from 2002-2011 were included in this study. Whole tissue sections of biopsy material and primary tumors were immunostained for pancytokeratin and CD8 or CD45RO. Stromal (s) and intraepithelial (i) T-cell infiltrates were analyzed for prediction of patient survival as well as clinical and pathological TNM-stage of the primary tumor. RESULTS: CD8 T-cell infiltration in the preoperative biopsy was significantly associated with favorable overall survival (CD8i p?=?0.0026; CD8s p?=?0.0053) in patients with primary CRC independently of TNM-stage and postoperative therapy (HR [CD8i]?=?0.55 (95% CI: 0.36-0.82), p?=?0.0038; HR [CD8s]?=?0.72 (95% CI: 0.57-0.9), p?=?0.0049). High numbers of CD8i in the biopsy predicted earlier pT-stage (p?<?0.0001) as well as absence of nodal metastasis (p?=?0.0015), tumor deposits (p?=?0.0117), lymphatic (p?=?0.008) and venous invasion (p?=?0.0433) in the primary tumor. Infiltration by CD45ROs cells was independently associated with longer survival (HR?=?0.76 (95% CI: 0.61-0.96), p?=?0.0231) and predicted absence of venous invasion (p?=?0.0025). CD8 counts were positively correlated between biopsies and the primary tumor (r?=?0.42; p?<?0.0001) and were reproducible between observers (ICC [CD8i]?=?0.95, ICC [CD8s]?=?0.75). For CD45RO, reproducibility was poor to moderate (ICC [CD45i]?=?0.16, ICC [CD45s]?=?0.49) and correlation with immune infiltration in the primary tumor was fair and non-significant (r[CD45s]?=?0.16; p?=?0.2864). For both markers, no significant relationship was observed with radiographic T-stage, N-stage or M-stage, indicating that assessment of T-cells in biopsy material can add additional information to clinical staging in the pre-operative setting. CONCLUSIONS: T-cell infiltration in pre-operative biopsy specimens of CRC is an independent favorable prognostic factor and strongly correlates with absence of nodal metastasis in the resection specimen. Quantification of CD8i is highly reproducible and allows superior prediction of clinicopathological features as compared to CD45RO. The assessment of CD8i infiltration in biopsies is recommended for prospective investigation.

Project description:Matrix Gla protein (MGP) was originally reported as a physiological suppressor of ectopia calcification and has also been reported to be associated with cancer. However, the relation between the biological functions of MGP and the immune response in colorectal cancer (CRC) remains unclear. Here, we investigated the regulatory role of MGP in the immune microenvironment of CRC. MGP expression in CRC samples was assessed by single-cell RNA sequencing and the Gene Expression Omnibus (GEO) database, and confirmed by quantitative real-time Polymerase Chain Reaction (qRT-PCR) and immunohistochemistry analysis of human CRC samples. The effect of MGP on proliferation and invasion of CRC cells was evaluated by in vitro assays involving MGP knockdown and overexpression. Luciferase reporter assay and chromatin immunoprecipitation (ChIP)-qPCR assay were performed to identify transcriptional regulatory sites of the nuclear factor kappa-B (NF-κB) and programmed cell death ligand 1 (PD-L1). In vivo experiments were performed in mouse model of CRC liver metastasis established via spleen injection. The results revealed that MGP was significantly upregulated in cancer cell clusters from the primary CRC or liver metastases, compared with that in the corresponding paracancerous tissues via single-cell RNA sequencing. MGP enriched intracellular free Ca2+ levels and promoted NF-κB phosphorylation, thereby activated PD-L1 expression to promote CD8+ T cell exhaustion in CRC. The luciferase reporter assay and ChIP-qPCR assay indicated that the transcriptional regulation of NF-κB upregulated PD-L1 expression. In vivo, MGP inhibition significantly decreased the rate of CRC liver metastasis, which was further reduced after combined therapy with αPD1 (anti-PD1). In conclusions, this study revealed that MGP can facilitate CD8+ T cell exhaustion by activating the NF-κB pathway, leading to liver metastasis of CRC. The combination of MGP knockdown and αPD1 can synergistically resist liver metastasis of CRC.

Project description:Background: Long noncoding RNA KCNQ1 opposite strand/antisense transcript 1 (lncRNA KCNQ1OT1) is abnormally expressed in various solid tumors. The purpose of this study was to explore the prognostic value and potential functional role of lncRNA KCNQ1OT1 across cancers. Methods: We performed a meta-analysis of published literature to evaluate the prognostic value of lncRNA KCNQ1OT1 across cancers. Verification, functional analysis, and genomic variation analysis were performed using the GEPIA, TIMER, and LnCeVar databases. According to the immune cell infiltration level, we established a prognostic model of lncRNA KCNQ1OT1 expression using public datasets of TIMER. We used quantitative real-time polymerase chain reaction (RT-qPCR) and western blot to detect the expression levels of lncRNA KCNQ1OT1 and the CD155 protein in colorectal cancer (CRC) tissues and cell lines. Then, a lncRNA KCNQ1OT1-knockdown cell line was cocultured to explore the role of lncRNA KCNQ1OT1 and CD155 in the T cell response by flow cytometric analysis. Results: Our results showed that the high expression of lncRNA KCNQ1OT1 was significantly related to poor overall survival across cancers, especially CRC. Interestingly, we found that COAD patients with high lncRNA KCNQ1OT1 expression and high CD8+ T cell infiltration levels had a worse prognosis than those with low lncRNA KCNQ1OT1 expression and high CD8+ T cell infiltration levels. Moreover, lncRNA KCNQ1OT1 and CD155 showed significantly higher expression in CRC tissue than in normal tissue, and lncRNA KCNQ1OT1 expression was positively correlated with CD155 expression in CRC. Finally, knockdown of lncRNA KCNQ1OT1 reduced CD155 expression in HCT116 and SW620 cells and enhanced the immune response in coculture with CD8+ T cells. Conclusions: High lncRNA KCNQ1OT1 expression is significantly correlated with poor prognosis of CRC patients and mediates the CD8+ T cell response in CRC. These findings indicate that lncRNA KCNQ1OT1 is a prognostic biomarker and potential immune therapeutic target for enhancing the CD8+ T cell response in CRC.

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Global Pattern of CD8⁺ T-Cell Infiltration and Exhaustion in Colorectal Cancer Predicts Cancer Immunotherapy Response.

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Dataset Information

Global Pattern of CD8+ T-Cell Infiltration and Exhaustion in Colorectal Cancer Predicts Cancer Immunotherapy Response.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Global Pattern of CD8⁺ T-Cell Infiltration and Exhaustion in Colorectal Cancer Predicts Cancer Immunotherapy Response.