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Tumor-specific cytotoxic T lymphocyte activity determines colorectal cancer patient prognosis.

ABSTRACT: The composition of tumor-targeted T cell infiltrates is a major prognostic factor in colorectal cancer (CRC) outcome; however, the functional role of these populations in prolonging patient survival remains unclear. Here, we evaluated 190 patients with CRC for the presence of functionally active tumor-infiltrating lymphocytes (TILs), the tumor specificity of these TILs, and the correlation between patient TILs and long-term survival. Using intracytoplasmic cytokine staining in conjunction with HLA multimers loaded with tumor peptide and antigen-specific cytokine secretion assays, we determined that TNF-? expression delineates a population of tumor antigen-specific (TA-specific) cytotoxic T lymphocytes (CTLs) present within tumors from patients with CRC. Upregulation of TNF-? expression in TILs strongly correlated with an increase in the total amount of intratumoral TNF-?, which is indicative of tumor-specific CTL activity. Moreover, a retrospective multivariate analysis of 102 patients with CRC, which had multiple immune parameters evaluated, revealed that increased TNF-? concentration was an independent prognostic factor. Together, these results indicate that the prognostic impact of T cell infiltrates for CRC maybe largely based on subpopulations of active TA-specific T cells within the tumor, suggesting causal implication for these cells in patient survival. Additionally, these results support the use of intratumoral TNF-?, which is indicative of T cell function, as a prognostic parameter for CRC.

SUBMITTER: Reissfelder C

PROVIDER: S-EPMC4319435 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Tumor-specific cytotoxic T lymphocyte activity determines colorectal cancer patient prognosis.

Reissfelder Christoph C Stamova Slava S Gossmann Christina C Braun Marion M Bonertz Andreas A Walliczek Ute U Grimm Mario M Rahbari Nuh N NN Koch Moritz M Saadati Maral M Benner Axel A Büchler Markus W MW Jäger Dirk D Halama Niels N Khazaie Khashayarsha K Weitz Jürgen J Beckhove Philipp P

The Journal of clinical investigation 20141222 2

The composition of tumor-targeted T cell infiltrates is a major prognostic factor in colorectal cancer (CRC) outcome; however, the functional role of these populations in prolonging patient survival remains unclear. Here, we evaluated 190 patients with CRC for the presence of functionally active tumor-infiltrating lymphocytes (TILs), the tumor specificity of these TILs, and the correlation between patient TILs and long-term survival. Using intracytoplasmic cytokine staining in conjunction with H ...[more]

PMID: 25562322

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Project description:BackgroundArtificial intelligence (AI) technology represented by deep learning has made remarkable achievements in digital pathology, enhancing the accuracy and reliability of diagnosis and prognosis evaluation. The spatial distribution of CD3 + and CD8 + T cells within the tumor microenvironment has been demonstrated to have a significant impact on the prognosis of colorectal cancer (CRC). This study aimed to investigate CD3 CT (CD3 + T cells density in the core of the tumor [CT]) prognostic ability in patients with CRC by using AI technology.MethodsThe study involved the enrollment of 492 patients from two distinct medical centers, with 358 patients assigned to the training cohort and an additional 134 patients allocated to the validation cohort. To facilitate tissue segmentation and T-cells quantification in whole-slide images (WSIs), a fully automated workflow based on deep learning was devised. Upon the completion of tissue segmentation and subsequent cell segmentation, a comprehensive analysis was conducted.ResultsThe evaluation of various positive T cell densities revealed comparable discriminatory ability between CD3 CT and CD3-CD8 (the combination of CD3 + and CD8 + T cells density within the CT and invasive margin) in predicting mortality (C-index in training cohort: 0.65 vs. 0.64; validation cohort: 0.69 vs. 0.69). The CD3 CT was confirmed as an independent prognostic factor, with high CD3 CT density associated with increased overall survival (OS) in the training cohort (hazard ratio [HR] = 0.22, 95% confidence interval [CI]: 0.12-0.38, P <0.001) and validation cohort (HR = 0.21, 95% CI: 0.05-0.92, P = 0.037).ConclusionsWe quantify the spatial distribution of CD3 + and CD8 + T cells within tissue regions in WSIs using AI technology. The CD3 CT confirmed as a stage-independent predictor for OS in CRC patients. Moreover, CD3 CT shows promise in simplifying the CD3-CD8 system and facilitating its practical application in clinical settings.

Project description:BACKGROUND:Colorectal cancer (CRC) is the second leading cancer killer in the US today and patients with metastatic disease have only a 14% 5-year survival. One of the most impactful recent advances in cancer therapy, immune checkpoint inhibition, has not been shown to be effective for the majority of these patients. In this study, we use The Cancer Genome Atlas (TCGA) and recently developed informatic-based tools to identify targets for immune based therapy in colorectal cancer patients. METHODS:Open access, pre-processed (level 3) mRNA data and clinical data from colorectal patients from the TCGA was downloaded from FireCloud. Using the Microenvironment Cell Populations-Counter method (MCP-Counter), cytotoxic lymphocyte scores were calculated for all patients. Patients were then grouped by cytotoxic lymphocyte score (High vs Low), pathologic stage, and location to identify differentially expressed genes. Pathway enrichment analysis was performed using Reactome to determine differentially expressed genes associated with immune pathways. Survival analysis was performed with identified differentially expressed genes. RESULTS:In the TCGA dataset, there are 461 colon and 172 rectal cancer patients. After stratifying patients by cytotoxic lymphocyte score, anatomical location, and stage, we found a significant number of differentially expressed genes. We identified one pathway, "immunoregulatory interactions between a lymphoid and non-lymphoid cell", that was highly enriched and included in all tumor locations and stages. Survival analysis performed with differentially expressed genes in this pathway identified 21 different genes associated with survival and cytotoxic lymphocyte infiltration, with ~?70% of these genes occurring in the metastatic right-sided CRC group. Specifically, all genes associated with survival in the metastatic right-sided colorectal cancer group with low cytotoxic lymphocyte scores positively impacted survival. CONCLUSIONS:Utilizing the TCGA, a publicly available dataset, and informatics-based analyses, we identified potential targets to improve immune based therapy in colorectal cancer. Additionally, we note the most targets in metastatic right-sided CRC patients, the patient group with the worst predicted survival. The results from this study demonstrate the ability of informatics-based analytic techniques to identify new therapeutic targets as well as improve patient selection for intervention, helping us to achieve the goals of precision-based oncology.

Dataset Information

Tumor-specific cytotoxic T lymphocyte activity determines colorectal cancer patient prognosis.

Publications

Tumor-specific cytotoxic T lymphocyte activity determines colorectal cancer patient prognosis.

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