scholarly journals Loss of survival advantage for deficient mismatch repair in patients with advanced colorectal cancer may be caused by changes in prognostic value of CD8+T cell

2020 ◽  
Author(s):  
Bingyan Wang ◽  
Fei Li ◽  
Limei Guo ◽  
Siyi Lu ◽  
Junren Ma ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Mismatch Repair ◽  
Prognostic Value ◽  
Disease Free Survival ◽  
Cd8 T Cell ◽  
Stage I ◽  
Stage Iii ◽  
Functional Changes ◽  
Deficient Mismatch Repair

Abstract Background: Patients with stage II deficient mismatch repair (dMMR) show a better prognosis than patients with colorectal cancer with proficient mismatch repair (pMMR). However, this beneficial effect is decreased in advanced stages of the disease. This study was conducted to investigate the prognostic value of dMMR and alterations in the tumour microenvironment.Methods: This was a matched retrospective cohort study. Thirty-two patients with stage III&IV dMMR matched with 32 patients with stage I&II dMMR and 64 patients with pMMR were evaluated. Immunohistochemistry analysis was performed for the 64 patients with dMMR to explore the expression and prognostic effect of CD3, CD4, CD8, and PD-L1.Results: Patients with stage III-IV dMMR showed no advantage in overall survival (OS) and disease-free survival (DFS) compared to patients with pMMR (P = 0.244, P = 0.667). No expression differences in CD3, CD4, CD8, and PD-L1 at the centre of the tumour (CT) or invasive margin (IM) were found between patients with stage I&II and stage III&IV dMMR. High CD3 expression at the CT and high CD3 an CD4 expression at the IM improved both OS and DFS. High CD8 expression showed opposite prognostic value in patients with stage I&II and III&IV dMMR. A similar tendency was observed for PD-L1 expression.Conclusion: Patients with stage III-IV dMMR showed no prognostic advantage over patients with pMMR. Expression of CD3, CD4, CD8, and PD-L1 was similar between stage I&II and III&IV dMMR CRC. High CD3 expression at the CT and high CD3 and CD4 expression at the IM can significantly improve patient prognosis. The opposite prognostic tendency of CD8 and PD-L1 for patients with stage I&II and III&IV dMMR may be relevant to CD8+T cell exhaustion and functional changes at inhibitory immune checkpoints.

scholarly journals Loss of survival advantage for deficient mismatch repair in patients with advanced colorectal cancer may be caused by changes in prognostic value of CD8+T cell expression

2020 ◽  
Author(s):  
Bingyan Wang ◽  
Fei Li ◽  
Limei Guo ◽  
Siyi Lu ◽  
Junren Ma ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Mismatch Repair ◽  
Prognostic Value ◽  
Disease Free Survival ◽  
Cd8 T Cell ◽  
Stage I ◽  
Stage Iii ◽  
Keywords Colorectal Cancer ◽  
Deficient Mismatch Repair

Abstract Background: Patients with stage II deficient mismatch repair (dMMR) show a better prognosis than patients with colorectal cancer with proficient mismatch repair (pMMR). However, this beneficial effect is decreased in advanced stages of the disease. This study was conducted to investigate the prognostic value of dMMR and alterations in the tumour microenvironment. Methods: This was a matched retrospective cohort study. Thirty-two patients with stage III&IV dMMR matched with 32 patients with stage I&II dMMR and 64 patients with pMMR were evaluated. Immunohistochemistry analysis was performed for the 64 patients with dMMR to explore the expression and prognostic effect of CD3, CD4, CD8, and PD-L1. Results: Patients with stage III-IV dMMR showed no advantage in overall survival (OS) and disease-free survival (DFS) compared to patients with pMMR (P = 0.244, P = 0.667). No expression differences in CD3, CD4, CD8, and PD-L1 at the centre of the tumour (CT) or invasive margin (IM) were found between patients with stage I&II and stage III&IV dMMR. High CD3 expression at the CT and high CD3 an CD4 expression at the IM improved both OS and DFS. High CD8 expression showed opposite prognostic value in patients with stage I&II and III&IV dMMR. A similar tendency was observed for PD-L1 expression. Conclusion: Patients with stage III-IV dMMR showed no prognostic advantage over patients with pMMR. Expression of CD3, CD4, CD8, and PD-L1 was similar between stage I&II and III&IV dMMR CRC. High CD3 expression at the CT and high CD3 and CD4 expression at the IM can significantly improve patient prognosis. The opposite prognostic tendency of CD8 and PD-L1 for patients with stage I&II and III&IV dMMR may be relevant to CD8+T cell exhaustion and functional changes at inhibitory immune checkpoints. Keywords: colorectal cancer, deficient mismatch repair, tumour-infiltrating lymphocyte, PD-L1, prognosis

Versican proteolysis as a key regulator of CD8+ T-cell infiltration in colorectal cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15082-e15082
Author(s):  
Dustin A. Deming ◽  
Chelsea Hope ◽  
Philip Emmerich ◽  
Adam Pagenkopf ◽  
Kristina Matkowskyj ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Mismatch Repair ◽  
Tumor Infiltrating Lymphocytes ◽  
Cd8 T Cell ◽  
Staining Intensity ◽  
Cell Infiltration ◽  
Tissue Samples ◽  
Tumor Bed ◽  
T Cell Infiltration

e15082 Background: Colorectal cancer (CRC) originates within immunologically complex microenvironments. To date the benefits of immunotherapy have been modest except in neoantigen-laden mismatch repair (MMR)-deficient tumors. Approaches to enhance tumor-infiltrating lymphocytes (TILS) in the tumor bed may substantially augment clinical immunotherapy responses. Proteolysis of the tolerogenic matrix proteoglycan versican (VCAN) generates a bioactive fragment, versikine, with putative immunostimulatory activities. Methods: Matched normal and CRC tissue samples were collected from 122 patients with cancers across all stages and locations throughout the colon and rectum. These samples were stained for VCAN, αDPEAAE (neoepitope generated in cleaving VCAN to versikine), and CD8 and scored by a pathologist. Tumors were classified as VCAN proteolysis-predominant (VPP) if their staining for total VCAN staining intensity was < 1+ and staining for VCAN proteolysis (αDPEAAE antibody) was > 2. Conversely, tumors were classified as VCAN proteolysis-weak (VPW) if intact VCAN staining intensity was > 1+ or αDPEAAE intensity was < 2+. IHC for mismatch repair (MMR) proteins was also performed. Results: Overall increased VCAN staining was observed in cancer versus (vs) normal tissue. VPP tumors had a 10 fold greater infiltration of CD8+ T-cells vs VPW cancers (p < 0.001). The correlation between VCAN proteolysis and CD8+ T-cell infiltration was maintained in both cancers with proficient (p) MMR and deficient (d) MMR. In both pMMR and dMMR, the VPP tumors had the greatest degree of CD8+ T-cell infiltration (Wilcoxon rank sum tests: pMMR p = 0.006; dMMR p = 0.03). Among the VPP tumors there was a greater degree of CD8+ T cell infiltration in the dMMR cancers vs pMMR cancers (35 versus 14.8 TILs per high power filed, p = 0.04). Nuclear CTNNB1, a marker for activation of WNT signaling, negatively correlated with CD8+ T cell infiltration( p = 0.014). In addition, VCAN accumulation correlated with the presence of nuclear CTNNB1 (p < 0.001) Conclusions: This is the first description indicating that VCAN proteolysis may shape CRC immune contexture and provide a rationale for testing VCAN proteolysis as a predictive and/or prognostic immune biomarker.

Prognostic value of PD-L1 expression in colorectal cancer.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 610-610
Author(s):  
Albert Y. Lin ◽  
Natalia B. Kouzminova ◽  
Thomas Chou
Keyword(s):  
Colorectal Cancer ◽  
Mismatch Repair ◽  
Prognostic Value ◽  
Cox Regression ◽  
Stage I ◽  
Rank Test ◽  
Cancer Tissue ◽  
P53 Overexpression ◽  
Entire Cohort ◽  
Programmed Death

610 Background: Growing evidence have shown promise for targeting programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling in several tumors. However, the role of PD-L1 expression in colorectal cancer (CRC) tumor cells and its interaction with other clinicopathologic factors remain elusive. Methods: We constructed a tissue microarray with paraffin-embedded primary colon cancer tissue (n=103; stage I, 22; II: 44; III: 37). Expression levels of biomarkers (PD-L1, EGFR, p53, Ki67, LEF1, VEGF, COX2, MMR – by IHC, and MiR-34a - by in situ hybridization), clinicopathologic variables and clinical outcomes were investigated. H-score evaluation of PD-L1 was performed. Tumors with an H score >55, derived using Cutoff Finder, were considered PD-L1 positive for use in Kaplan-Meier survival analysis with log-rank test and in Cox regression models for recurrence-free survival (RFS) and overall survival (OS). Results: Median follow-up time for the entire cohort was 4.7 years (range 0.1-20.8). Positive PLD1 was identified in 89% of cases. As a group, cases with positive PD-L1 expression had better OS than those with negative expressions (12.2 vs 3.3 years) (p = 0.043), especially in cases with mismatch repair proficiency (MMR-P, 12.1 vs 1.0 years) (p <0.001). Negative PD-L1 expression in cases who had no chemotherapy was associated with worse outcome for OS (p=0.001) and RFS (p=0.008). There was no significant association between PD-L1 expression and gender, age, tumor size, pathologic stage or tumor grade. However, PD-L1 expression was significantly associated with MiR-34a (p<0.001) and p53 overexpression (p=0.008) with a trend toward association in cases with mismatch repair proficiency (MMR-P, p=0.053). Conclusions: Our results suggest that negative PD-L1 expression appears to have negative prognostic value with worse RFS and OS in stage I - III CRC patients, especially those who had not received any chemotherapy. Given a recent study suggesting p53/miR-34a/PD-L1 axis as a novel mechanism of immune evasion, and strong correlation in the PD-L1/p53 and PD-L1/miR-334a expressions in our cohort, further investigation of their interactions is warranted that may lead to identifying their predictive value for immuno/chemotherapy.

scholarly journals Phenotype-Genotype Correlation in Colorectal Cancer: A Real-Life Study

2021 ◽  
pp. 1-9
Author(s):  
Catarina Frias-Gomes ◽  
Ana Carla Sousa ◽  
Inês Rolim ◽  
Ana Raquel Henriques ◽  
Francisco Branco ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mismatch Repair ◽  
Early Stage ◽  
Small Sample Size ◽  
Real Life ◽  
Disease Free Survival ◽  
Small Sample ◽  
Stage I ◽  
Curative Surgery ◽  
Genetic Characteristics

<b><i>Background and Aims:</i></b> Colorectal cancer (CRC) is a heterogeneous disease with distinctive genetic pathways, such as chromosomal instability, microsatellite instability and methylator pathway. Our aim was to correlate clinical and genetic characteristics of CRC patients in order to understand clinical implications of tumour genotype. <b><i>Methods:</i></b> Single-institution retrospective cohort of patients who underwent curative surgery for CRC, from 2012 to 2014. <i>RAS</i> and <i>BRAF</i> mutations were evaluated with the real-time PCR technique Idylla®. Mismatch repair deficiency (dMMR) was characterized by absence of MLH1, MSH6, MSH2 and/or PMS2 expression, evaluated by tissue microarrays. Overall survival (OS) and disease-free survival (DFS) were assessed using survival analysis. <b><i>Results:</i></b> Overall, 242 patients were included (males 57.4%, age 69.3 ± 12.9 years; median follow-up 49 months). <i>RAS</i>-mutated tumours were associated with reduced DFS (<i>p</i> = 0.02) and OS (<i>p</i> = 0.045) in stage I–III CRC. <i>BRAF</i>-mutated tumours were more predominant in females and in the right colon, similarly to dMMR tumours. BRAF status did not influence OS (4 years)/DFS (3.5 years) in stage I–III disease. However, after relapse, length of survival was 3.5 months in <i>BRAF</i>-mutated tumours in contrast to 18.6 months in <i>BRAF</i> wild-type tumours (<i>p</i> = NS). No germline mutations in mismatch repair genes were so far identified in the patients with dMMR tumours. Molecular phenotype (<i>RAS, BRAF</i> and MMR) did not influence OS in metastatic patients. Our small sample size may be a limitation of the study. <b><i>Conclusion:</i></b> In our cohort, <i>RAS</i>-mutated tumours were associated with worse DFS and OS in early-stage CRC, whereas the remaining molecular variables had no prognostic influence.

Treatment outcome and prognostic factors for primary nasal lymphoma.

1995 ◽  
Vol 13 (3) ◽  
pp. 666-670 ◽  
Author(s):  
R Liang ◽  
D Todd ◽  
T K Chan ◽  
E Chiu ◽  
A Lie ◽  
...  
Keyword(s):  
T Cell ◽  
Complete Remission ◽  
Combination Chemotherapy ◽  
Disease Free Survival ◽  
Stage I ◽  
Stage Iii ◽  
Chinese Patients ◽  
Low Grade ◽  
Bulky Disease ◽  
Nasal Lymphoma

PURPOSE To report our experience managing a large series of Chinese patients with primary nasal lymphoma. PATIENTS AND METHODS From January 1975 to December 1993, 100 patients (median age, 50 years) with newly diagnosed primary nasal lymphoma were studied. There were four low-grade, 62 intermediate-grade, nine high-grade, and 25 unclassifiable lymphomas. Immunophenotyping was performed in 45 patients: eight B cell, 35 T cell, and two uncertain. All cases of angiocentric lymphoma that were typed were T cell. Fifty-two patients had stage I disease, 15 had stage II, four had stage III, and 29 had stage IV. Only 15 patients had B symptoms (weight loss, night sweats, and/or fever), and 11 had bulky disease. Thirty-nine patients with clinically localized stage I and II disease received local radiotherapy alone (before 1980), and the remaining 28 stage I and II patients received combination chemotherapy followed by local radiotherapy. The 33 patients with advanced stage III and IV disease were given combination chemotherapy, and additional radiotherapy was given to five of them who had bulky local disease. RESULTS Significantly higher complete remission rates were observed in patients with early stages of disease and those without B symptoms. Superior disease-free survival after complete remission was observed in patients with stage I/II disease. Univariate factors associated with a better overall survival included age less than 60 years, stage I disease, and absence of B symptoms. Survival was significantly better in the subgroup of patients with stage I disease. CONCLUSION Patients with nasal lymphoma, especially those with advanced disease, seemed to have a poor prognosis, and their clinical outcome was not improved significantly by the use of chemotherapy instead of radiotherapy or the use of doxorubicin-containing chemotherapeutic regimens.

The association of CD8+ T-cell infiltration and PD-L1 expression with prognosis of Chinese pulmonary large cell neuroendocrine carcinoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21003-e21003
Author(s):  
Ye Li ◽  
Xinying Shi ◽  
Jinliang Wang ◽  
Beibei Mao ◽  
Jie Li ◽  
...  
Keyword(s):  
T Cell ◽  
Neuroendocrine Carcinoma ◽  
Univariate Analysis ◽  
Disease Free Survival ◽  
Large Cell ◽  
Cd8 T Cell ◽  
Large Cell Neuroendocrine Carcinoma ◽  
Stage I ◽  
Cell Infiltration ◽  
T Cell Infiltration

e21003 Background: Pulmonary large cell neuroendocrine carcinoma (LCNCE) is a high-grade neuroendocrine tumor with poor prognosis. The genomic profile and immune feature of LCNEC have been reported in many studies. However, the relationship between immune microenvironment and the prognosis of LCNEC patients is poorly understood. Our study was aimed to examine the infiltration of CD8+ T cell and PD-L1+ cells in LCNEC patients, and explore whether CD8+T cell and PD-L1+ cells are related to LCNEC patients’ prognosis. Methods: 37 eligible LCNEC patients (stage I-III) with received the treatment of surgical operation (27 among 37 patients underwent adjuvant radiochemotherapy) were included, tumor tissues were collected from the first medical center of Chinese PLA General Hospital. Multiplex immunohistochemistry (Multi IHC) was performed using the antibodies of CD8 and PD-L1. The univariate and multivariate cox proportional hazards analyses were used to assess the association between the abundance of CD8+T cell and PD-L1+ cells with the clinical outcome of LCNEC patients. Results: Patients were divided into high and low group using the median positive percentage of CD8 or PD-L1 as cutoff. The univariate analysis showed that patients with stromal high CD8+ T cell infiltration or stage I had significantly longer disease free survival (DFS) (CD8, p = 0.03; stage I, p = 0.036), and patients with high PD-L1 expression in stroma region, I stage, adjvant radiochemotherapy had notably increased overall survival (OS) (p = 0.049, p = 0.031, p = 0.023, respectively). However, the infiltration of CD8+ T cell or PD-L1 expression in total or tumor region had no correlation with survival of LCNEC patients. Furthermore, multivariate analysis demonstrated that low CD8+ T cell density in stroma region was an independent risk factor for PFS (p = 0.03), advanced TNM stage (II-III stage, p = 0.0009) and low stromal PD-L1 expression were independent risk factors for OS (p = 0.013). Conclusions: High infiltration of CD8+ T cell or PD-L1+ cell in stroma region were independent good prognosis factors of LCNEC patients. However, these findings need a larger LCNEC cohort to validate.

scholarly journals Prognostic significance of CD8+ T-cells density in stage III colorectal cancer depends on SDF-1 expression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alexandros Lalos ◽  
Ali Tülek ◽  
Nadia Tosti ◽  
Robert Mechera ◽  
Alexander Wilhelm ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
T Cells ◽  
T Cell ◽  
Cell Density ◽  
Cd8 T Cells ◽  
Prognostic Significance ◽  
Cd8 T Cell ◽  
Stage Iii ◽  
Weak Correlation

AbstractSince colorectal cancer (CRC) remains one of the most common malignancies, a tremendous amount of studies keep taking place in this field. Over the past 25 years, a notable part of the scientific community has focused on the association between the immune system and colorectal cancer. A variety of studies have shown that high densities of infiltrating CD8+ T-cells are associated with improved disease-free and overall survival in CRC. Stromal cell-derived factor-1 (SDF-1) is a protein that regulates leukocyte trafficking and is variably expressed in several healthy and malignant tissues. There is strong evidence that SDF-1 has a negative prognostic impact on a variety of solid tumors. However, the existing data do not provide sufficient evidence that the expression of SDF-1 has an influence on CRC. Knowing nowadays, that the microenvironment plays a crucial role in the development of cancer, we hypothesized that the expression of SDF-1 in CRC could influence the prognostic significance of CD8+ T-cells, as an indicator of the essential role of the immune microenvironment in cancer development. Therefore, we explored the combined prognostic significance of CD8+ T-cell density and SDF-1 expression in a large CRC collective. We analyzed a tissue microarray of 613 patient specimens of primary CRCs by immunohistochemistry (IHC) for the CD8 + T-cells density and the expression of SDF-1 by tumor cells and tumor-infiltrating immune cells. Besides, we analyzed the expression of SDF-1 at the RNA level in The Cancer Genome Atlas cohort. We found that the combined high CD8+ T-cell infiltration and expression of SDF-1 shows a favorable 5-year overall survival rate (66%; 95% CI 48–79%) compared to tumors showing a high expression of CD8+ T-cell only (55%; 95% CI 45–64%; p = 0.0004). After stratifying the patients in nodal negative and positive groups, we found that the prognostic significance of CD8+ T-cell density in nodal positive colorectal cancer depends on SDF-1 expression. Univariate and multivariate Hazard Cox regression survival analysis considering the combination of both markers revealed that the combined high expression of SDF-1 and CD8+ T-cell density was an independent, favorable, prognostic marker for overall survival (HR = 0.34, 95% CI 0.17–0.66; p = 0.002 and HR = 0.45, 95% CI 0.23–0.89; p = 0.021, respectively). In our cohort there was a very weak correlation between SDF-1 and CD8+ T-cells (rs = 0.13, p = 0.002) and in the trascriptomic expression of these two immune markers display a weak correlation (rs = 0.28, p < 0.001) which was significantly more pronounced in stage III cancers (rs = 0.40, p < 0.001). The combination of high CD8+ T-cell density and expression of SDF-1 represents an independent, favorable, prognostic condition in CRC, mostly in patients with stage III disease.

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