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Comparison of the prognostic value of measures of the tumor inflammatory cell infiltrate and tumor-associated stroma in patients with primary operable colorectal cancer.

ABSTRACT: The aim of the present study was to compare the clinical utility of two measures of the inflammatory cell infiltrate - a H&E-based assessment of the generalized inflammatory cell infiltrate (the Klintrup-Mäkinen (KM) grade), and an immunohistochemistry-based assessment of combined CD3⁺ and CD8⁺ T-cell density (the "Immunoscore"), in conjunction with assessment of the tumor stroma percentage (TSP) in patients undergoing resection of stage I-III colorectal cancer (CRC). Two hundred and forty-six patients were identified from a prospectively maintained database of CRC resections in a single surgical unit. Assessment of KM grade and TSP was performed using full H&E sections. CD3⁺ and CD8⁺ T-cell density was assessed on full sections and the Immunoscore calculated. KM grade and Immunoscore were strongly associated (p < 0.001). KM grade stratified cancer-specific survival (CSS) from 88% to 66% (p = 0.002) and Immunoscore from 93% to 61% (p < 0.001). Immunoscore further stratified survival of patients independent of KM grade from 94% (high KM, Im4) to 60% (low KM, Im0/1). Furthermore, TSP stratified survival of patients with a weak inflammatory cell infiltrate (low KM: from 75% to 47%; Im0/1: from 71% to 38%, both p < 0.001) but not those with a strong inflammatory infiltrate. On multivariate analysis, only Immunoscore (HR 0.44, p < 0.001) and TSP (HR 2.04, p < 0.001) were independently associated with CSS. These results suggest that the prognostic value of an immunohistochemistry-based assessment of the inflammatory cell infiltrate is superior to H&E-based assessment in patients undergoing resection of stage I-III CRC. Furthermore, assessment of the tumor-associated stroma, using TSP, further improves prediction of outcome.

SUBMITTER: Park JH

PROVIDER: S-EPMC4839333 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Comparison of the prognostic value of measures of the tumor inflammatory cell infiltrate and tumor-associated stroma in patients with primary operable colorectal cancer.

Park J H JH McMillan D C DC Edwards J J Horgan P G PG Roxburgh C S D CS

Oncoimmunology 20160321 3

The aim of the present study was to compare the clinical utility of two measures of the inflammatory cell infiltrate - a H&E-based assessment of the generalized inflammatory cell infiltrate (the Klintrup-Mäkinen (KM) grade), and an immunohistochemistry-based assessment of combined CD3<sup>+</sup> and CD8<sup>+</sup> T-cell density (the "Immunoscore"), in conjunction with assessment of the tumor stroma percentage (TSP) in patients undergoing resection of stage I-III colorectal cancer (CRC). Two h ...[more]

PMID: 27141369

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Project description:BackgroundExisting high-risk factors are insufficient to accurately predict the postoperative recurrence risk of stage II colorectal cancer (CRC). The discovery of additional prognostic markers may be the key to improving the current status of stage II CRC treatment. The present study aimed to evaluate the relationship among desmoplastic reaction (DR), tumor budding (TBd), the tumor-stroma ratio (TSR) and their prognostic value for relapse-free survival (RFS).MethodsIn this study, 207 patients with histologically confirmed stage II CRC from January 2012 to August 2018 were retrospectively reviewed from a single center; the cohort was divided into subgroups based on low or high TSR, and low, intermediate or high DR and TBd. Kaplan-Meier curve analysis and log-rank test were applied to examine RFS among subgroups. Univariate and multivariate Cox proportional hazards analyses were used to identify independent factors associated with RFS, and a nomogram was subsequently developed.ResultsAbnormal CA242, CEA, T4 stage, presence of hypertension, internal obstruction or perforation (IOP), lymphovascular or/and perineural invasion (PNI), number of nodes examined less than 12, low-frequency microsatellite instability (MSI-L), higher Ki-67 and immature DR were associated with a lower RFS. In multivariable analysis, DR (HR =2.111; 95% CI: 1.184-3.766; P=0.011), LVI (HR =1.919; 95% CI: 1.004-3.669; P=0.049) and PNI (HR =2.724; 95% CI: 1.362-5.448; P=0.005) were prognostic factors for RFS. On this basis, a nomogram that integrated DR and clinicopathologic predictors for predicting RFS passed the calibration and had an area under the curve of 0.826.ConclusionsThe prognostic significance of DR outperformed TBd and TSR, therefore, we recommend adding DR as a biomarker in routine pathological reports. The novel nomogram combining these factors may be used as a reliable and effective tool for the prediction of RFS in stage II CRC, thus helping optimize therapeutic regimens under cooperation of oncologists and surgeons. Further multicentric studies are required for validation of this novel, simple and cost-effective prognostic model.

Project description:Colorectal cancer (CRC) ranks as the second leading cause of cancer-related mortality globally and is the third most prevalent cancer. The effective treatment of CRC is challenged by tumor drug resistance, underscoring the urgent need for novel therapeutic strategies. It is well recognized that epigenetic modifications, particularly DNA methylation, significantly contribute to the initiation and advancement of CRC. Tumors frequently exhibit hypermethylation of specific gene promoters alongside a general hypomethylation of genomic DNA. In normal tissues, gene promoters, particularly those of tumor suppressor genes, are typically unmethylated, whereas they are often hypermethylated in cancerous tissues. Previous studies have identified the methylation status of the CpG island within the SLC30A10 gene as a reliable biomarker for CRC. Notably, a hypermethylated phenotype is inversely correlated with SLC30A10 expression. However, the precise functional implications of SLC30A10 suppression in the context of CRC progression remain to be elucidated.). The investigation of molecular pathways involved in metal metabolism in CRC has not been conducted previously at the transcriptomic level. Furthermore, the relationship between the mutational characteristics of tumors—such as individual mutations, mutational burden, and microsatellite instability—and the activity of genes related to metal metabolic pathways has not been explored. This project aims to be the first to examine the antitumor potential of modulating the transport systems for manganese and zinc ions in CRC. The molecular function of SLC30A10 is to export zinc (Zn) and manganese (Mn) ions from the cell. Additionally, SLC30A10 plays a crucial role in mitigating Mn-induced cytotoxicity and facilitates Zn transport to early endosomes while promoting endosomal recirculation to avert Zn toxicity. Our findings indicate that overexpression of SLC30A10 is correlated with the knockout of its functional antagonist, SLC39A14 in the HuTu80 and HCT-15 cell lines.

Project description:Colorectal cancer (CRC) is one of the most common cancers in France (36,000 new cases / year) and nearly 16,000 people die each year from this disease. The lymph node involvement of the surgical specimen is today the main tool on which is based the adjuvant treatment decision after curative surgical resection. The study of new predictive factors to identify patients at risk for developing a local or metastatic recurrence is therefore a major challenge. It is now clear that the immune system plays a role in the control of tumor’s development, and it was shown that there was a correlation between the presence of a CD3+ T-lymphocyte infiltrate in colorectal cancers and patient survival. Preliminary studies suggest an important role of regulatory T-lymphocyte in the modulation of the antitumor immune response. The aim of our study is to follow a cohort of patients operated for colon cancer with curative intent to highlight the prognostic characteristics of the tumoral infiltrate by various lymphocyte populations (particularly T-lymphocytes but also B-lymphocytes and regulatory lymphocytes). It will be performed a preoperative analysis of blood circulating lymphocytes with antibodies specific for different cell populations (CD3, CD4, CD8, CD56, CD16, CD19, CD2) and stage of activation (CD25, CD69, HLA-DR ) or differentiation (CD24, CD38, CD27, CD103, CD62L, CCR7, CD45RA / RO, IgD). The presence of regulatory T-lymphocytes will also be analyzed. It will be performed on tumor sample a Tissue Microarrays for immunohistochemical study to determine the presence of different lymphocyte populations. We systematically study the markers CD68 (monocytes / macrophages), CD56 (NK cells), CD20 and CD79a (B cells / plasma cells), CD3 (T cells), CD8 (cytotoxic T), CD4 (helper T) FoxP3 (regulatory T), cytotoxicity of CD8 markers (Fas ligand, perforin and granzyme) and MHC I (antigen presentation) to explore the innate and adaptive immune responses. For each section, the different zones will be analyzed (center and invasive margin and healthy tissue). The main objective of the study is the influence of the tumor infiltration rate by CD3 + T cells on disease free survival at 2-years in patients with non-metastatic colon cancer resection. The secondary objective is to search a correlation between the rate of T-lymphocytes on preoperative blood sample and on tumor sample.

Dataset Information

Comparison of the prognostic value of measures of the tumor inflammatory cell infiltrate and tumor-associated stroma in patients with primary operable colorectal cancer.

Publications

Comparison of the prognostic value of measures of the tumor inflammatory cell infiltrate and tumor-associated stroma in patients with primary operable colorectal cancer.

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