scholarly journals Prognostic significance of myeloid immune cells and their spatial distribution in the colorectal cancer microenvironment

2021 ◽  
Vol 9 (4) ◽  
pp. e002297
Author(s):  
Juha P Väyrynen ◽  
Koichiro Haruki ◽  
Sara A Väyrynen ◽  
Mai Chan Lau ◽  
Andressa Dias Costa ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Immune Cell ◽  
Prognostic Significance ◽  
Myeloid Cell ◽  
Cancer Microenvironment ◽  
Hla Dr ◽  
Specific Mortality ◽  
Cancer Specific Mortality

BackgroundMyeloid cells represent an abundant yet heterogeneous cell population in the colorectal cancer microenvironment, and their roles remain poorly understood.MethodsWe used multiplexed immunofluorescence combined with digital image analysis to identify CD14+ monocytic and CD15+ granulocytic cells and to evaluate their maturity (HLA-DR and CD33), immunosuppressive potential (ARG1) and proximity to cytokeratin (KRT)-positive tumor cells in 913 colorectal carcinomas. Using covariate data of 4465 incident colorectal cancers in two prospective cohort studies, the inverse probability weighting method was used with multivariable-adjusted Cox proportional hazards models to assess cancer-specific mortality according to ordinal quartiles (Q1–Q4) of myeloid cell densities. Immune cell–tumor cell proximity was measured with the nearest neighbor method and the G-cross function, which determines the likelihood of any tumor cell having at least one immune cell of the specified type within a certain radius.ResultsHigher intraepithelial (Ptrend=0.0002; HR for Q4 (vs Q1), 0.48, 95% CI 0.31 to 0.76) and stromal (Ptrend <0.0001; HR for Q4 (vs Q1), 0.42, 95% CI 0.29 to 0.63) densities of CD14+HLA-DR+ cells were associated with lower colorectal cancer-specific mortality while, conversely, higher intraepithelial densities of CD14+HLA-DR− cells were associated with higher colorectal cancer-specific mortality (Ptrend=0.0003; HR for Q4 (vs Q1), 1.78, 95% CI 1.25 to 2.55). Spatial analyses indicated that CD15+ cells were located closer to tumor cells than CD14+ cells, and CD14+HLA-DR+ cells were closer to tumor than CD14+HLA-DR− cells (p<0.0001). The G-cross proximity measurement, evaluating the difference in the likelihood of any tumor cell being colocated with at least one CD14+HLA-DR+ cell versus CD14+HLA-DR− cell within a 20 µm radius, was associated with lower colorectal cancer-specific mortality (Ptrend <0.0001; HR for Q4 (vs Q1), 0.37, 95% CI 0.24 to 0.57).ConclusionsMyeloid cell populations occur in spatially distinct distributions and exhibit divergent, subset-specific prognostic significance in colorectal cancer, with mature CD14+HLA-DR+ and immature CD14+HLA-DR− monocytic phenotypes most notably showing opposite associations. These results highlight the prognostic utility of multimarker evaluation of myeloid cell infiltrates and reveal a previously unrecognized degree of spatial organization for myeloid cells in the immune microenvironment.

scholarly journals Effects of cancer screening restart strategies after COVID-19 disruption

2021 ◽  
Vol 124 (9) ◽  
pp. 1516-1523
Author(s):  
Lindy M. Kregting ◽  
Sylvia Kaljouw ◽  
Lucie de Jonge ◽  
Erik E. L. Jansen ◽  
Elleke F. P. Peterse ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Screening ◽  
Colorectal Cancer Screening ◽  
Catching Up ◽  
Incidence And Mortality ◽  
Specific Mortality ◽  
Cancer Specific Mortality ◽  
Catch Up ◽  
Microsimulation Models ◽  
The Impact

Abstract Background Many breast, cervical, and colorectal cancer screening programmes were disrupted due to the COVID-19 pandemic. This study aimed to estimate the effects of five restart strategies after the disruption on required screening capacity and cancer burden. Methods Microsimulation models simulated five restart strategies for breast, cervical, and colorectal cancer screening. The models estimated required screening capacity, cancer incidence, and cancer-specific mortality after a disruption of 6 months. The restart strategies varied in whether screens were caught up or not and, if so, immediately or delayed, and whether the upper age limit was increased. Results The disruption in screening programmes without catch-up of missed screens led to an increase of 2.0, 0.3, and 2.5 cancer deaths per 100 000 individuals in 10 years in breast, cervical, and colorectal cancer, respectively. Immediately catching-up missed screens minimised the impact of the disruption but required a surge in screening capacity. Delaying screening, but still offering all screening rounds gave the best balance between required capacity, incidence, and mortality. Conclusions Strategies with the smallest loss in health effects were also the most burdensome for the screening organisations. Which strategy is preferred depends on the organisation and available capacity in a country.

scholarly journals Tumor Infiltration by OX40+ Cells Enhances the Prognostic Significance of CD16+ Cell Infiltration in Colorectal Cancer

2020 ◽  
Vol 27 (1) ◽  
pp. 107327482090338
Author(s):  
Fabian Haak ◽  
Isabelle Obrecht ◽  
Nadia Tosti ◽  
Benjamin Weixler ◽  
Robert Mechera ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Immune Cell ◽  
Cox Regression ◽  
Prognostic Significance ◽  
Tumor Necrosis Factor Receptor ◽  
Tissue Microarrays ◽  
Cell Infiltration ◽  
Prognostic Impact ◽  
Cox Regression Analysis ◽  
Kaplan Meier

Objectives: Analysis of tumor immune infiltration has been suggested to outperform tumor, node, metastasis staging in predicting clinical course of colorectal cancer (CRC). Infiltration by cells expressing OX40, a member of the tumor necrosis factor receptor family, or CD16, expressed by natural killer cells, monocytes, and dendritic cells, has been associated with favorable prognosis in patients with CRC. We hypothesized that assessment of CRC infiltration by both OX40+ and CD16+ cells might result in enhanced prognostic significance. Methods: Colorectal cancer infiltration by OX40 and CD16 expressing cells was investigated in 441 primary CRCs using tissue microarrays and specific antibodies, by immunohistochemistry. Patients’ survival was evaluated by Kaplan-Meier and log-rank tests. Multivariate Cox regression analysis, hazard ratios, and 95% confidence intervals were also used to evaluate prognostic significance of OX40+ and CD16+ cell infiltration. Results: Colorectal cancer infiltration by OX40+ and CD16+ cells was subclassified into 4 groups with high or low infiltration levels in all possible combinations. High levels of infiltration by both OX40+ and CD16+ cells were associated with lower pT stage, absence of peritumoral lymphocytic (PTL) inflammation, and a positive prognostic impact. Patients bearing tumors with high infiltration by CD16+ and OX40+ cells were also characterized by significantly longer overall survival, as compared with the other groups. These results were confirmed by analyzing an independent validation cohort. Conclusions: Combined infiltration by OX40+ and CD16+ immune cells is an independent favorable prognostic marker in CRC. The prognostic value of CD16+ immune cell infiltration is significantly improved by the combined analysis with OX40+ cell infiltration.

scholarly journals High-dimensional cytometric analysis of colorectal cancer reveals novel mediators of antitumour immunity

Gut ◽  
2019 ◽  
Vol 69 (4) ◽  
pp. 691-703 ◽  
Author(s):  
Natasja L de Vries ◽  
Vincent van Unen ◽  
Marieke E Ijsselsteijn ◽  
Tamim Abdelaal ◽  
Ruud van der Breggen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Lymph Nodes ◽  
Single Cell ◽  
Immune Cell ◽  
Γδ T Cells ◽  
High Dimensional ◽  
Hla Dr ◽  
Healthy Mucosa ◽  
Immune Contexture

ObjectiveA comprehensive understanding of anticancer immune responses is paramount for the optimal application and development of cancer immunotherapies. We unravelled local and systemic immune profiles in patients with colorectal cancer (CRC) by high-dimensional analysis to provide an unbiased characterisation of the immune contexture of CRC.DesignThirty-six immune cell markers were simultaneously assessed at the single-cell level by mass cytometry in 35 CRC tissues, 26 tumour-associated lymph nodes, 17 colorectal healthy mucosa and 19 peripheral blood samples from 31 patients with CRC. Additionally, functional, transcriptional and spatial analyses of tumour-infiltrating lymphocytes were performed by flow cytometry, single-cell RNA-sequencing and multispectral immunofluorescence.ResultsWe discovered that a previously unappreciated innate lymphocyte population (Lin–CD7+CD127–CD56+CD45RO+) was enriched in CRC tissues and displayed cytotoxic activity. This subset demonstrated a tissue-resident (CD103+CD69+) phenotype and was most abundant in immunogenic mismatch repair (MMR)-deficient CRCs. Their presence in tumours was correlated with the infiltration of tumour-resident cytotoxic, helper and γδ T cells with highly similar activated (HLA-DR+CD38+PD-1+) phenotypes. Remarkably, activated γδ T cells were almost exclusively found in MMR-deficient cancers. Non-activated counterparts of tumour-resident cytotoxic and γδ T cells were present in CRC and healthy mucosa tissues, but not in lymph nodes, with the exception of tumour-positive lymph nodes.ConclusionThis work provides a blueprint for the understanding of the heterogeneous and intricate immune landscape of CRC, including the identification of previously unappreciated immune cell subsets. The concomitant presence of tumour-resident innate and adaptive immune cell populations suggests a multitargeted exploitation of their antitumour properties in a therapeutic setting.

scholarly journals Prognostic Significance of Immune Cell Populations Identified by Machine Learning in Colorectal Cancer Using Routine Hematoxylin and Eosin–Stained Sections

2020 ◽  
Vol 26 (16) ◽  
pp. 4326-4338 ◽  
Author(s):  
Juha P. Väyrynen ◽  
Mai Chan Lau ◽  
Koichiro Haruki ◽  
Sara A. Väyrynen ◽  
Andressa Dias Costa ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Machine Learning ◽  
Immune Cell ◽  
Prognostic Significance ◽  
Cell Populations ◽  
Hematoxylin And Eosin

Tumor-collagen digital proximity signature to indicate prognosis in diffuse large B-cell lymphoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e19073-e19073
Author(s):  
Talha Qaiser ◽  
Matthew Pugh ◽  
Sandra Margielewska ◽  
Robert Hollows ◽  
Paul Murray ◽  
...  
Keyword(s):  
Overall Survival ◽  
Tumor Cell ◽  
B Cell ◽  
Tumor Cells ◽  
Cell Lymphoma ◽  
Prognostic Significance ◽  
B Cell Lymphoma ◽  
Automated Image Analysis ◽  
Large B Cell Lymphoma ◽  
Large B Cell

e19073 Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous tumor that originates from normal B-cells. Despite the use of combination chemotherapy, around 40% of DLBCL patients die (de Jonge, et al. European Journal of Cancer, 2016). Limited studies have investigated the role of collagen in the acellular tumor microenvironment. In this study, we present a novel digital signature of the proximity of tumor cells and collagen-VI (COL6) that can predict overall survival (OS) in DLBCL patients. To the best of our knowledge, this is the first study of its kind to employ automated image analysis. Methods: The proposed digital proximity signature (DPS) aggregates summary-level statistics from the entire whole slide image (WSI) and serves as a marker of regions, categorizing weak, moderate, significant, and strong tumor-collagen proximity and can be described as a surrogate for signaling. To accomplish this, we developed a novel artificial intelligence (AI) based multi-task model for simultaneous detection and classification of tumor cells and another bespoke method for automatically identifying COL6 fiber. The tumor-collagen proximity analysis was then performed by aggregating tumor cell statistics within the vicinity of COL6 fibres. Finally, the prognostic significance of DPS for OS in DLBCL was investigated with Kaplan-Meier analysis, stratifying patients into two groups based on the median of the DPS values. Results: We took WSIs of DLBCL tissue slides for 32 cases immunohistochemically stained with COL6 and Hematoxylin counterstain. The AI model for tumor cell identification achieved a high F1-score of 0.84, outperforming recent single-task learning models. Our results show that strong proximity of COL6 and tumor cells is linked to better OS in DLBCL patients ( p = 0.03). Conclusions: Our novel digitally computed COL6-tumor proximity signature shows prognostic significance for overall survival on a pilot dataset of 32 DLBCL patients. We are further validating the utility of this novel signature as a prognostic biomarker in larger cohorts of DLBCL patients.

Physical Activity and Survival After Colorectal Cancer Diagnosis

2006 ◽  
Vol 24 (22) ◽  
pp. 3527-3534 ◽  
Author(s):  
Jeffrey A. Meyerhardt ◽  
Edward L. Giovannucci ◽  
Michelle D. Holmes ◽  
Andrew T. Chan ◽  
Jennifer A. Chan ◽  
...  
Keyword(s):  
Physical Activity ◽  
Colorectal Cancer ◽  
Cancer Survival ◽  
Hazard Ratio ◽  
Adjusted Hazard Ratio ◽  
Recreational Physical Activity ◽  
Activity Assessment ◽  
Specific Mortality ◽  
Cancer Specific Mortality ◽  
Overall Mortality

Purpose Physically active individuals have a lower risk of developing colorectal cancer but the influence of exercise on cancer survival is unknown. Patients and Methods By a prospective, observational study of 573 women with stage I to III colorectal cancer, we studied colorectal cancer–specific and overall mortality according to predefined physical activity categories before and after diagnosis and by change in activity after diagnosis. To minimize bias by occult recurrences, we excluded women who died within 6 months of their postdiagnosis physical activity assessment. Results Increasing levels of exercise after diagnosis of nonmetastatic colorectal cancer reduced cancer-specific mortality (P for trend = .008) and overall mortality (P for trend = .003). Compared with women who engaged in less than 3 metabolic equivalent task [MET] -hours per week of physical activity, those engaging in at least 18 MET-hours per week had an adjusted hazard ratio for colorectal cancer–specific mortality of 0.39 (95% CI, 0.18 to 0.82) and an adjusted hazard ratio for overall mortality of 0.43 (95% CI, 0.25 to 0.74). These results remained unchanged even after excluding women who died within 12 and 24 months of activity assessment. Prediagnosis physical activity was not predictive of mortality. Women who increased their activity (when comparing prediagnosis to postdiagnosis values) had a hazard ratio of 0.48 (95% CI, 0.24 to 0.97) for colorectal cancer deaths and a hazard ratio of 0.51 (95% CI, 0.30 to 0.85) for any-cause death, compared with those with no change in activity. Conclusion Recreational physical activity after the diagnosis of stages I to III colorectal cancer may reduce the risk of colorectal cancer–specific and overall mortality.

scholarly journals Prognostic significance of isolated tumor cells in patients with colorectal cancer in recent 10-year studies

2013 ◽  
Vol 1 (4) ◽  
pp. 582-592 ◽  
Author(s):  
YOSHITO AKAGI ◽  
TETSUSHI KINUGASA ◽  
YOSUKE ADACHI ◽  
KAZUO SHIROUZU
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cells ◽  
Prognostic Significance ◽  
Isolated Tumor Cells

scholarly journals Downregulation of PLK4 Expression Induces Cellular Dormancy in Colorectal Cancer via Mesenchymal-to-epithelial Transition

2020 ◽  
Author(s):  
Xiangdong Tian ◽  
Dongming Liu ◽  
Dejun Zhou ◽  
Lisha Qi ◽  
Zhiqiang Han ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Risk Factors ◽  
Cell Cycle ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Quiescent State ◽  
Aggressive Tumor ◽  
Cell Dormancy

Abstract Background: Reactivation of dormant tumor cells is a critical step in the recurrence of many cancers, including colorectal cancer (CRC). Polo-like kinases 4 (PLK4), a central regulator of the cell cycle and proliferation, is a validated oncogene in tumorigenesis. However, the roles of PLK4 in tumor cell dormancy and reactivation still need to be further explored.Methods: The expression level of PLK4 was determined by immunohistochemical staining, Western blotting (WB) and quantitative real-time PCR (qRT-PCR). PLK4-dependent clinicopathological risk factors and the prognosis of CRC were characterized with 122 clinical samples. The roles of PLK4 in tumor cell dormancy, cell cycle progression, proliferation and invasion were determined by molecular and cell biology methods in vitro and in vivo.Results: The expression of PLK4 was dramatically increased in CRCs and positively correlated with aggressive tumor behavior and clinicopathological risk factors. Downregulation of PLK4 expression contributed to restoring phenotypically aggressive tumor cells to a quiescent state, and this transformation was likely regulated by mesenchymal-to-epithelial transformation (MET) progression in vitro and in vivo.Conclusions: This study elucidates the mechanisms involving PLK4 depletion in the induction and maintenance of CRC dormancy, which are very important in terms of both clinical significance and application value.

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