Prognostic significance of CD8+ T cell and macrophage peritumoral infiltration in colorectal cancer

2003 ◽  
Author(s):  
Yukihiro Funada ◽  
Tsuyoshi Noguchi ◽  
Ryuichi Kikuchi ◽  
Shinsuke Takeno ◽  
Yuzo Uchida ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Prognostic Significance ◽  
Cd8 T Cell

scholarly journals Prognostic significance of SDF-1 in colorectal cancer depends on CD8+ T-cell density

2020 ◽  
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 ◽  
High Expression ◽  
Prognostic Impact

Abstract Background: Since 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 colorectal cancer (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 colorectal cancer (CRC). However, based on a significant correlation of SDF-1 and CD8+ T cells in a previous study (r=0.53, p<0.0001), we hypothesized that the prognostic significance of SDF-1 in CRC could depend on the immune microenvironment. Therefore, we explored the combined prognostic significance of SDF-1 expression and CD8+ T cell density in a large CRC collective. Methods: We analyzed a tissue microarray (TMA) of 613 patient specimens of primary CRCs by immunohistochemistry (IHC) for the expression of SDF-1 by tumor cells and tumor-infiltrating immune cells (TICs) and CD8+ T-cells. Besides, we analyzed the expression of SDF-1 at the RNA level in The Cancer Genome Atlas cohort (TCGA). Results: We found that the the combined high expression of SDF-1 and CD8+ T-cell infiltration shows a favorable 5-year overall survival rate (66%; 95%CI=48–79%) compared to tumors showing a high expression of CD8+ T-cells only (55%; 95%CI=45–64%; p=0.0004). High expression of SDF-1 and CD8+ T-cells infiltration was significantly associated with a favorable prognosis also in a validation group (p=0.016). 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 cells 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 a spearman’s correlation analysis from the TCGA cohort, SDF-1 also correlated significantly with CD8+ T cells (r=0.28). Conclusions: SDF-1 high /CD8 high density represents an independent, favorable, prognostic condition in CRC, most likely due to an effective antigen-specific immune response.

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.

scholarly journals 342 Combining enadenotucirev and nivolumab increased tumour immune cell infiltration/activation in patients with microsatellite-stable/instability-low metastatic colorectal cancer in a phase 1 study

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A368-A369
Author(s):  
David Krige ◽  
Marwan Fakih ◽  
Lee Rosen ◽  
Ding Wang ◽  
Wael Harb ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Metastatic Colorectal Cancer ◽  
Cd8 T Cell ◽  
Post Treatment ◽  
Institutional Review Board ◽  
Cell Infiltration ◽  
Link Type ◽  
T Cell Infiltration ◽  
Institutional Review

BackgroundMicrosatellite-stable (MSS) and instability-low (MSI-L) metastatic colorectal cancer (mCRC) are typically characterised as ”immune-excluded/desert” tumour microenvironments lacking T-cell infiltration. Anti-PD-1 monotherapy has little clinical benefit in MSS/MSI-L mCRC1 and knowledge of the effects of PD-1 inhibition on T-cell activation/infiltration in this population is limited. Novel combination therapies to overcome anti-PD-1 resistance are required. SPICE is a multicentre, open-label, phase 1 study of the tumour-selective chimeric Ad11/Ad3 group B oncolytic adenovirus enadenotucirev plus nivolumab in patients with metastatic/advanced epithelial tumours refractory to standard therapy. Preliminary data from patients with MSS/MSI-L mCRC demonstrated a median overall survival of 14 months, manageable tolerability and intratumoural T-cell infiltration.2 Here we characterise the immunological effects of tumour re-engineering with enadenotucirev in combination with nivolumab in patients with MSS/MSI-L mCRC.MethodsPatients received increasing doses and/or cycles of intravenous enadenotucirev followed by up to 8 cycles of nivolumab as previously described.2 Wherever possible, pre- and post-treatment (~5 weeks post-first enadenotucirev) biopsies were collected; samples were analysed using immunohistochemistry and automated image analysis. Peripheral blood mononuclear cell immunophenotyping (multiparameter flow cytometry) and serum cytokines were assessed at multiple times.Results43 patients with mCRC were treated (86% MSS/MSI-L; 14% unknown). Among the 13 patients (12/13 MSS/MSI-L; 1/13 unknown) with matched biopsies, 11 had increased intratumoural and stromal CD8+ T-cell infiltration in post-treatment biopsies (median [Q1-Q3] fold changes 6.5× [1.5–25.4] and 1.9× [1.5–3.9], respectively; figure 1). CD4+ T-cell density increased in 10/13 patients and 8/13 patients had increased proportions of PD-L1+ immune cells. Increases in CD8 T-cell proliferation (Ki67; 7/9 patients) and cytolytic activity (Granzyme B; 7/13 patients) markers were seen. 4/13 patients converted from a ”desert” to an ”inflamed” immune phenotype (pathologist scored CD8/pan-cytokeratin staining). Immunophenotyping showed trends towards increased T-cell activation (CD38+ and HLA-DR+ CD8+ T cell populations) post-treatment (9/10 patients), including in one patient who had only received enadenotucirev prior to sampling. Persistent increases in inflammatory cytokines (IFNγ, IL-12p70, IL-17a) were seen in two patients from ~Day 15, including one who achieved a sustained objective response.Abstract 342 Figure 1Tumour immune cell infiltration following treatment with enadenotucirev plus nivolumabConclusionsThese data show that intravenous enadenotucirev plus nivolumab can induce immune infiltration/activation within MSS/MSI-L mCRC. These encouraging findings suggest that immune activation can be achieved even in ”immune-excluded/desert” tumours. SPICE has been closed following completion of dose-escalation. Efforts are now focused on the development of next-generation variants of enadenotucirev designed to further re-programme the tumour microenvironment by expressing immune-enhancer transgenes (T-SIGn vectors); these studies are ongoing (NCT04830592, NCT04053283, NCT03852511).AcknowledgementsThis study was funded by PsiOxus Therapeutics Limited and Bristol Myers Squibb. Medical writing support: Lola Parfitt, MRes, of PsiOxus Therapeutics Limited.Trial RegistrationEudraCT number2017-001231-39NCT number: NCT02636036ReferencesKawazoe A, Kuboki Y, Shinozaki E, et al. Multicenter phase I/II trial of napabucasin and pembrolizumab in patients with metastatic colorectal cancer (EPOC1503/SCOOP trial). Clin Cancer Res 2020;26:5887–5894.Fakih M, Wang D, Harb W, et al. SPICE: a phase I multicenter study of enadenotucirev in combination with nivolumab in tumors of epithelial origin: an analysis of the metastatic colorectal cancer patients in the dose escalation phase. Ann Oncol 2019:30(suppl_5):v252.Ethics ApprovalThe study was approved by the WCG Institutional Review Board (study approval number 20152656), UCLA Institutional Review Board (study approval number IRB#15-002010), Vanderbilt Institutional Review Board (study approval number IRB #171453) and Henry Ford Institutional Review Board (study approval number IRB #10349).

scholarly journals Intrinsic β-catenin signaling suppresses CD8+ T-cell infiltration in colorectal cancer

2019 ◽  
Vol 115 ◽  
pp. 108921 ◽  
Author(s):  
Junli Xue ◽  
Xuetao Yu ◽  
Liqiong Xue ◽  
Xiaoxiao Ge ◽  
Wei Zhao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
T Cell Infiltration

scholarly journals The correlation of BER protein, IRF3 with CD8+ T cell and their prognostic significance in upper tract urothelial carcinoma

2019 ◽  
Vol Volume 12 ◽  
pp. 7725-7735 ◽  
Author(s):  
Lin-ang Wang ◽  
Bo Yang ◽  
Wen Rao ◽  
Hualiang Xiao ◽  
Dong Wang ◽  
...  
Keyword(s):  
T Cell ◽  
Urothelial Carcinoma ◽  
Prognostic Significance ◽  
Cd8 T Cell ◽  
Upper Tract Urothelial Carcinoma ◽  
Upper Tract

scholarly journals The T-box transcription factor eomesodermin controls CD8 T cell activity and lymph node metastasis in human colorectal cancer

Gut ◽  
2007 ◽  
Vol 56 (11) ◽  
pp. 1572-1578 ◽  
Author(s):  
I. Atreya ◽  
C. C Schimanski ◽  
C. Becker ◽  
S. Wirtz ◽  
H. Dornhoff ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Transcription Factor ◽  
Lymph Node ◽  
T Cell ◽  
Lymph Node Metastasis ◽  
Cell Activity ◽  
Cd8 T Cell ◽  
Human Colorectal Cancer ◽  
T Box ◽  
Node Metastasis

Su2037 CD8+ T-Cell Infiltration in Epithelial and Stromal Tissues of MSI Colorectal Cancer Patients

2016 ◽  
Vol 150 (4) ◽  
pp. S617
Author(s):  
Lakshmi Kannan ◽  
Hassan Ashktorab ◽  
Edward L. Lee ◽  
Babak Shokrani ◽  
Akbar Soleimani ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Cancer Patients ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Colorectal Cancer Patients

Predicting CD8+ T-cell infiltration in colorectal cancer using versican proteolysis across molecular profiles.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 189-189
Author(s):  
Katherine Anne Johnson ◽  
Philip Emmerich ◽  
Kristina A. Matkowskyj ◽  
Dustin A. Deming
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Tumor Infiltrating Lymphocytes ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
Molecular Profile ◽  
High Power Field ◽  
Kras Mutations ◽  
T Cell Infiltration ◽  
The Impact

189 Background: The clinical indications for immunotherapies continue to increase across cancer types. In colorectal cancer (CRC), there has been little progress in the use of these therapies outside of mismatch repair deficient cancers (dMMR). However, even in dMMR cancers only a minority actually respond to the FDA-approved anti-PD1 agents. The tumor microenvironment is increasingly implicated in the resistance of cancers to immune-based therapies. Our group has previously described that accumulation of a matrix proteoglycan, versican, correlates with a reduction in CD8+ T-cell infiltration in CRCs, while proteolysis of versican, releasing the bioactive fragment versikine, correlates with increased infiltration. Here we examine the impact of pathogenic mutations on the utility of MMR status and versican proteolysis to predict CD8+ T-cell infiltration. Methods: Matched normal colon and CRC tissues from 122 patients were stained for versican, versikine, MLH1, MSH2, MSH6, PMS2, CNNB1, and CD8. Each was reviewed by a blinded GI surgical pathologist and CD8 quantified as tumor infiltrating lymphocytes (TILs) per high power field (hpf). 107 of the CRC samples were available for sequencing using the Qiagen Comprehensive Cancer Panel examining 160 genes across cancer relevant hotspots. The molecular profile was correlated with the IHC staining. Results: As previously reported, dMMR tumors had higher CD8+ T-cell infiltration. This trend persisted across dMMR genotypes (dMMR vs proficient (p)MMR p = 0.0016). Versican proteolysis correlated with increased CD8+ T cell infiltration in dMMR and pMMR cancers and was present in cancers with/without APC, TP53, and KRAS mutations. Across common mutations, cancers with the versican proteolysis predominant phenotype had more CD8+ T-cell infiltration than those without (APC mutant (mt): 11.82 vs 1.97 CD8+ TILs/hpf, p < 0.001; KRAS mt: 9.39 vs 3.08, p = 0.15; BRAF mt: 25.00 vs 7.50, p = 0.13; TP53 mt: 8.61 vs 1.63, p < 0.001). Conclusions: Across common mutations, versican proteolysis predicts CD8+ T-cell infiltration in both dMMR and pMMR CRC. Further investigation into whether this increase in infiltration will lead to greater immunotherapy response is warranted.

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