| 1. |
- Aleksandrova, Krasimira, et al.
(author)
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Development and validation of a lifestyle-based model for colorectal cancer risk prediction : the LiFeCRC score
- 2021
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In: BMC Medicine. - : Springer Science and Business Media LLC. - 1741-7015. ; 19:1
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Journal article (peer-reviewed)abstract
- Background: Nutrition and lifestyle have been long established as risk factors for colorectal cancer (CRC). Modifiable lifestyle behaviours bear potential to minimize long-term CRC risk; however, translation of lifestyle information into individualized CRC risk assessment has not been implemented. Lifestyle-based risk models may aid the identification of high-risk individuals, guide referral to screening and motivate behaviour change. We therefore developed and validated a lifestyle-based CRC risk prediction algorithm in an asymptomatic European population. Methods: The model was based on data from 255,482 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) study aged 19 to 70 years who were free of cancer at study baseline (1992–2000) and were followed up to 31 September 2010. The model was validated in a sample comprising 74,403 participants selected among five EPIC centres. Over a median follow-up time of 15 years, there were 3645 and 981 colorectal cancer cases in the derivation and validation samples, respectively. Variable selection algorithms in Cox proportional hazard regression and random survival forest (RSF) were used to identify the best predictors among plausible predictor variables. Measures of discrimination and calibration were calculated in derivation and validation samples. To facilitate model communication, a nomogram and a web-based application were developed. Results: The final selection model included age, waist circumference, height, smoking, alcohol consumption, physical activity, vegetables, dairy products, processed meat, and sugar and confectionary. The risk score demonstrated good discrimination overall and in sex-specific models. Harrell’s C-index was 0.710 in the derivation cohort and 0.714 in the validation cohort. The model was well calibrated and showed strong agreement between predicted and observed risk. Random survival forest analysis suggested high model robustness. Beyond age, lifestyle data led to improved model performance overall (continuous net reclassification improvement = 0.307 (95% CI 0.264–0.352)), and especially for young individuals below 45 years (continuous net reclassification improvement = 0.364 (95% CI 0.084–0.575)). Conclusions: LiFeCRC score based on age and lifestyle data accurately identifies individuals at risk for incident colorectal cancer in European populations and could contribute to improved prevention through motivating lifestyle change at an individual level.
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| 2. |
- Berntsson, Jonna, et al.
(author)
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Expression and prognostic significance of the polymeric immunoglobulin receptor in epithelial ovarian cancer
- 2014
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In: Journal of Ovarian Research. - : Springer Science and Business Media LLC. - 1757-2215. ; 7:1, s. 26-
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Journal article (peer-reviewed)abstract
- Background: High expression of the polymeric immunoglobulin receptor (PIGR) has previously been associated with a favourable prognosis in a few cancer forms, but its expression and relationship with clinical outcome in epithelial ovarian cancer (EOC) has not yet been reported. The aim of this study was therefore to examine the clinicopathological correlates and prognostic significance of PIGR expression in EOC. Methods: After an initial screening in the Human Protein Atlas portal, a validated antibody was selected for extended analysis of immunohistochemical PIGR expression in tissue microarrays with tumours from 154 incident cases of EOC from two pooled prospective population-based cohorts. Subsets of corresponding benign-appearing fallopian tubes (n = 38) and omental metastases (n = 33) were also analysed. Kaplan-Meier analysis and Cox regression analysis were applied to examine the impact of PIGR expression on overall survival (OS) and ovarian cancer-specific survival (OCSS). Results: PIGR expression was significantly higher in fallopian tubes compared to primary tumours and metastases (p < 0.001) and lower in carcinoma of the serous subtype compared to other carcinomas (p < 0.001). PIGR expression was significantly associated with lower grade (p = 0.001), mucinous histological subtype (p = 0.002), positive progesterone receptor expression (p = 0.009) and negative or low Ki-67 expression (p = 0.003). Kaplan-Meier analysis revealed a significantly improved OS (p = 0.013) and OCSS (p = 0.009) for patients with tumours displaying high expression of PIGR. These associations were confirmed in unadjusted Cox regression analysis (HR = 0.48; 95% CI 0.26-0.87; p = 0.015 for OS and HR = 0.43, 95% CI 0.22-0.82; p = 0.011 for OCSS) but did not remain significant after adjustment for age, grade and clinical stage. Conclusions: This study provides a first demonstration of PIGR expression in human fallopian tubes, primary EOC tumours and metastases. High tumour-specific expression of PIGR was found to be associated with a favourable prognosis in unadjusted, but not in adjusted, analysis. These findings are novel and merit further investigation.
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| 3. |
- Berntsson, Jonna, et al.
(author)
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Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in colorectal cancer : Relationship with sidedness and prognosis
- 2018
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In: OncoImmunology. - 2162-4011. ; 7:8
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Journal article (peer-reviewed)abstract
- Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 has been demonstrated to confer a prognostic value in colorectal cancer (CRC), but no studies have investigated whether this association differs according to tumour location. In this study, immunohistochemical expression of PD-1 and PD-L1 was analysed in tissue microarrays with primary tumours from 557 incident CRC cases from a prospective population-based cohort. Univariable and multivariable Cox regression analyses, adjusted for age, sex, TNM stage, differentiation grade and vascular invasion, were applied to determine the impact of biomarker expression on 5-year overall survival (OS), in the entire cohort and in subgroup analysis of right colon, left colon, and rectum. High PD-L1 expression on tumour-infiltrating immune cells was an independent factor of a prolonged OS in the entire cohort (hazard ratio [HR] = 0.49; 95% confidence interval [CI] CI 0.35 – 0.68), and in tumours of the right colon (HR = 0.43; 95% CI 0.25 – 0.74) and the left colon (HR = 0.28; 95% CI 0.13 – 0.61), but not in rectal cancer. Tumour-specific PD-L1-expression was not prognostic, neither in the full cohort nor according to tumour location. High immune cell-specific PD-1 expression was associated with a prolonged OS in the entire cohort and in tumours of the right colon, but not in the left colon or rectum, and only in univariable analysis. In conclusion, these results demonstrate that immune cell-specific PD-L1 and PD-1 expression is prognostic in a site-dependent manner, whereas tumour-specific PD-L1-expression is not prognostic in CRC.
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| 4. |
- Berntsson, Jonna, et al.
(author)
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Pre-diagnostic anthropometry, sex, and risk of colorectal cancer according to tumor immune cell composition
- 2019
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In: OncoImmunology. - 2162-4011. ; 8:12
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Journal article (peer-reviewed)abstract
- Obesity is a well-established risk factor for colorectal cancer (CRC), but the association with the tumor microenvironment has been sparsely described. Herein, we examined the relationship between pre-diagnostic anthropometry and CRC risk according to tumor immune cell composition, with particular reference to potential sex differences. The density of different immune cell subsets was assessed by immunohistochemistry in tissue microarrays with tumors from 584 incident CRC cases in a prospective, population-based cohort (n = 28098). Multivariable Cox regression models, adjusted for age, smoking, alcohol intake, and educational level, were applied to calculate risk of immune marker-defined CRC in relation to quartiles of pre-diagnostic height, weight, body mass index (BMI), waist and hip circumferences, waist-hip ratio (WHR), and body fat percentage (BFP). Obesity was all over significantly associated with risk of CRC with low density of FoxP3+ T cells and low programmed cell-death protein 1 (PD-L1) expression on tumor cells, but with high density of CD8+ T cells and CD20+ B cells. In women, obesity was significantly associated with risk of PD-L1 high tumors (p= 0.009 for weight, p= 0.039 for BMI). Contrastingly, in men, obesity defined by all anthropometric factors was significantly associated with PD-L1 low tumors (p= 0.005 for weight, p = 0.002 for BMI, p<0.001 for waist, p= 0.011 for hip, p<0.001 for WHR, and p= 0.004 for BFP). In summary, obesity appears to influence the immune landscape of CRC, possibly in a sex-dependent manner. Thus, anthropometry and sex may be important factors to take into account when assessing the prognostic or predictive value of relevant complementary immune biomarkers.
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| 5. |
- Berntsson, Jonna, et al.
(author)
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Prognostic impact of tumour-infiltrating B cells and plasma cells in colorectal cancer
- 2016
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 139:5, s. 1129-1139
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Journal article (peer-reviewed)abstract
- Multiple studies have described associations between infiltrating immune cells and prognosis in cancer; however, the clinical relevance has most often been attributed to the T-cell linage. This study aimed to further investigate the clinicopathological correlates and prognostic impact of B cell and plasma cell infiltration in CRC. Immunohistochemical expression of CD20, CD138 and immunoglobulin kappa C (IGKC) was analysed in tissue microarrays with tumours from 557 incident cases of CRC from a prospective population-based cohort. Kaplan-Meier analysis and Cox regression analysis were used to determine the impact of CD20, CD138 and IGKC expression on 5-year overall survival. Immune cell-specific CD20, CD138, and IGKC expression correlated significantly with lower T-stage (p < 0.001, p < 0.001, and p=0.006, respectively). A higher density of CD201 cells correlated significantly with an improved OS (HR=0.53, 95% CI 0.36-0.78), remaining significant in multivariable analysis adjusted for age, TNM stage, differentiation grade and vascular invasion (HR=0.51; 95% CI 0.33-0.80). Immune cell-specific CD138 and IGKC expression correlated significantly with an improved OS in univariable Cox regression analysis; however, these associations did not remain significant in multivariable analysis. Finally, tumour cell-specific CD138 expression was found to be an independent factor of poor prognosis (HR 1.52; 95% CI 1.03-2.24). The results from the present study demonstrate that B cell infiltration in CRC has a significant impact on tumour progression and prognosis. These findings supplement and extend the current knowledge of the immune landscape in colorectal cancer, and merit further study.
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| 6. |
- Berntsson, Jonna, et al.
(author)
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The clinical impact of tumour-infiltrating lymphocytes in colorectal cancer differs by anatomical subsite : A cohort study
- 2017
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In: International Journal of Cancer. - : WILEY. - 0020-7136 .- 1097-0215. ; 141:8, s. 1654-1666
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Journal article (peer-reviewed)abstract
- Accumulating evidence demonstrates an association between dense infiltration of lymphocytes and prognosis in colorectal cancer (CRC), but whether this prognostic impact differs by tumour location remains unknown. This study investigated the prognostic impact of cytotoxic and regulatory T cells in CRC, with particular referennfiltrating T cce to the anatomical subsite of the primary tumour. The density of CD3(+), CD8(+) and FoxP3(+) tumour-iells was calculated in tissue microarrays with tumours from 557 incident CRC cases from a prospective population-based cohort. Kaplan-Meier and Cox regression analyses were applied to determine the impact of high and low lymphocyte density on 5-year overall survival, in subgroup analysis of right colon, left colon and rectum. High CD8(+) cell density was a favourable prognostic factor for patients with right-sided colon tumours (hazard ratio [HR]=0.53, 95% confidence interval [CI] 0.29-0.95), independent of age, sex, TNM stage, differentiation grade and vascular invasion, with a significant prognostic interaction between CD8(+) cells and right-sidedness (p=0.031). High FoxP3(+) cell density was an independent favourable prognostic factor only in patients with rectal tumours (HR=0.54, 95% CI 0.30-0.99), and CD3(+) cell density was an independent favourable prognostic factor for tumours in the right colon and rectum, but there was no significant prognostic interaction between CD3(+) or FoxP3(+) cells and sidedness. These results demonstrate that the prognostic impact of tumour-infiltrating lymphocytes in CRC differs by primary tumour site, further indicating that tumour location may be an important factor to take into consideration in therapeutic decisions, including eligibility for immunotherapy.
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| 7. |
- Berntsson, Jonna
(author)
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The immune microenvironment of colorectal cancer - Relationship with survival, sidedness, and pre-diagnostic anthropometry
- 2019
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Doctoral thesis (other academic/artistic)abstract
- Colorectal cancer (CRC) is the third most common cancer worldwide. Increasing evidence suggests that CRC should be considered a heterogeneous disease, with multiple differences between proximal and distal tumours. The immune system may, depending on the context, promote or inhibit tumour growth, and different immune cell subsets have been found to be associated with impaired or improved prognosis in CRC. The major aim of this thesis was to investigate the prognostic impact of different immune cell signatures in CRC, with particular reference to primary tumour location, and, furthermore, to perform a characterization of immune cell signatures in relation to anthropometric factors.The study cohort for Papers I-III consists of all 626 cases of CRC in the prospective, population-based cohort Malmö Diet and Cancer Study (MDCS) from 1991 up until December 31, 2008, of which tumours from 557 cases were available for tissue microarray construction, including 201 (36.2%) right-sided and 145 (26.1%) left-sided colon cancers, and 209 (37.7%) rectal cancers. Immunohistochemistry was applied to assess the density of tumour-infiltrating immune cells. For Paper IV, the analyses were restricted to the 584 cases included in the European Prospective Investigation into Cancer (EPIC) cohort, of which the MDCS forms part. Anthropometric measurements were taken at baseline. Cox proportional hazards regression models were applied to study the hazard ratios for survival, and the risk of CRC with particular immune cell compositions.Paper I shows that dense infiltration of B cells is an independent favourable prognostic factor in CRC. Paper II demonstrates that high infiltration of cytotoxic T cells is an independent favourable prognostic factor only in right-sided colon cancer, whereas high infiltration of regulatory T cells is an independent prognostic factor only in rectal cancer. Moreover, re-analysis of the data from paper I revealed that the prognostic impact of B cells is only evident in right-sided tumours.Paper III demonstrates that high expression of programmed cell deaht ligand 1 (PD-L1) on immune cells is an independent favourable prognostic factor only in patients with right-sided and left-sided colon cancer. Paper IV shows that obesity, indicated by several anthropometric factors, is associated with risk of CRC with high infiltration of B cells and cytotoxic T cells but with low infiltration of regulatory T cells in both sexes, albeit with weaker associations in women. Moreover, the results show that obesity is associated with risk of CRC with low PD-L1 expression on immune cells in men, but with high PD-L1 expression on immune cells in women.These results show that the prognostic impact of tumour-infiltrating immune cells in CRC differs according to primary tumour location. It is also demonstrated that obesity might influence the immune microenvironment of CRC. In summary, the findings indicate that primary tumour location, anthropometric factors, and sex are all important factors to include in future studies on the tumour microenvironment of CRC.
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| 8. |
- Blom, Anna M, et al.
(author)
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Expression of Cartilage Oligomeric Matrix Protein in colorectal cancer is an adverse prognostic factor and correlates negatively with infiltrating immune cells and PD-L1 expression
- 2023
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In: Frontiers in Immunology. - 1664-3224. ; 14
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Journal article (peer-reviewed)abstract
- INTRODUCTION: Cartilage Oligomeric Matrix Protein (COMP) is an oncogenic protein that has been associated with a decrease in infiltrating T-cells in periampullary adenocarcinoma. This study aimed to investigate whether this is also the case for colorectal cancer (CRC) and to evaluate the relationship between COMP expression and clinopathological features.METHODS: Immunohistochemistry was used to determine the expression levels of COMP in tumor cells and stroma in primary tumors from a cohort of 537 CRC patients. The expression of immune cell markers, including CD3+, CD8+, FoxP3+, CD68+, CD56+, CD163+, and PD-L1, was evaluated previously. Tumor fibrosis was assessed by Sirius Red staining and evaluation of collagen fiber organization.RESULTS: COMP expression correlated positively with TNM-stage and grade of differentiation. Patients with CRC expressing high levels of COMP had significantly shorter OS than those with low COMP expression (p<0.0001), and fewer infiltrating T-cells were detected in tumors with high COMP expression. Additionally, a negative correlation was identified between the expression of COMP and PD-L1 on both tumor cells and immune cells. Cox regression analysis showed that tumors expressing high levels of COMP had significantly shorter OS, independent of all evaluated immune cell markers. Tumor fibrosis was correlated with high expression of COMP in the stroma (p<0.0001), and tumors with high levels of COMP expression and denser fibrosis displayed more sparse immune cell infiltration.DISCUSSION: The results suggest that COMP expression in CRC may exert an immune regulatory effect by increasing dense fibrosis and decreasing immune cell infiltration. These findings support the notion that COMP is an important factor in the development and progression of CRC.
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| 9. |
- Fristedt, Richard, et al.
(author)
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Prognostic impact of tumour-associated B cells and plasma cells in oesophageal and gastric adenocarcinoma
- 2016
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In: Journal of Gastrointestinal Oncology. - : AME Publishing Company. - 2078-6891 .- 2219-679X. ; 7:6, s. 848-859
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Journal article (peer-reviewed)abstract
- Background: While it is well established that the cell-mediated immune response plays an important role in cancer progression and spread, the role of the humoral immune response in this regard has been less studied. According to the existing literature, dense infiltration of B cells or plasma cells appears to correlate mainly with an improved prognosis in several types of cancer, but their prognostic impact in oesophageal and gastric cancer has not yet been described. Methods: Immunohistochemistry was applied on tissue microarrays (TMA) to assess the stromal density of B cells (CD20+) and plasma cells [CD138+ or immunoglobulin kappa C (IGKC+)] in chemo-/radiotherapy-naive tumours from a consecutive cohort of 174 patients with resected oesophageal or gastric adenocarcinoma. Cox proportional hazard's modelling was applied to examine the impact of the investigated markers on overall survival (OS) and time to recurrence (TTR). Results: In curatively treated patients with oesophageal adenocarcinoma, high expression of IGKC was an independent predictor of a prolonged OS [hazard ratio (HR) 0.10; 95% confidence interval (CI), 0.02-0.57], and TTR (HR 0.15; 95% CI, 0.03-0.71). In curatively treated patients with gastric adenocarcinoma, high expression of IGKC independently predicted a prolonged OS (HR 0.46; 95 % CI, 0.24-0.87) and TTR (HR 0.46; 95% CI, 0.21-0.98). Expression of CD20 was not prognostic, and CD138 expression was only prognostic in unadjusted analysis of TTR in gastric cancer. Conclusions: These results demonstrate, for the first time, that abundant infiltration of IGKC+ plasma cells independently predicts a prolonged survival in both oesophageal and gastric cancer.
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| 10. |
- Lundgren, Sebastian, et al.
(author)
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Prognostic impact of tumour-associated B cells and plasma cells in epithelial ovarian cancer
- 2016
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In: Journal of Ovarian Research. - : Springer Science and Business Media LLC. - 1757-2215. ; 9
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Journal article (peer-reviewed)abstract
- Background: The critical role of the immune system in controlling cancer progression has become evident and immune modulatory therapy is now approved for clinical use. However, while the majority of studies on the inflammatory tumour microenvironment have focused on the cellular immune response, in particular the prognostic and predictive role of various T cell infiltrates, the role of the humoral immune response in this context has long been overlooked. This study aimed to investigate the clinicopathological correlates and prognostic impact of B cell and plasma cell infiltration in epithelial ovarian cancer (EOC). Methods: Immunohistochemical expression of immunoglobulin kappa C (IGKC), CD20 and CD138 was analysed in tissue microarrays with tumours from 154 incident cases of EOC from two pooled prospective population-based cohorts. Subsets of corresponding benign-appearing fallopian tubes (n = 38) and omental metastases (n = 33) were also analysed. Kaplan-Meier analysis and Cox regression analysis were used to determine the impact of immune-cell specific IGKC, CD20 and CD138 expression on overall survival and ovarian cancer-specific survival. Results: High IGKC expression correlated significantly with expression of CD20 (p = 0.001) and CD138 (p = 0.035). Expression of IGKC as well as CD138 was significantly higher in primary tumours than in fallopian tubes (p = 0.004 and p = 0.001, respectively). High CD20 and CD138 expression correlated significantly with high tumour grade (p = 0.032 and p = 0.030, respectively). CD20 and IGKC expression was not prognostic but univariable Cox regression analysis revealed high CD138 expression to correlate with a significantly reduced overall survival (HR = 2.20; 95 % CI 1.34-3.55; p-0.001) as well as ovarian cancer-specific survival (HR = 1.95; 95 % CI 1.28-2.98; p = 0.002). The prognostic impact was independent of established clinical parameters (age, grade, clinical stage) as shown in multivariable analysis (HR = 2.28; 95 % CI 1.39-3.75; p = 0.001). Conclusions: In conclusion, our results demonstrate that plasma cell infiltration in epithelial ovarian cancer has a significant impact on tumour progression and prognosis. The important role of the humoral immune system merits further study and may be harnessed as immune modulatory strategies in cancer therapy.
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