| 1. |
- Jeremiasen, Martin, et al.
(författare)
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Tumor-Associated CD68+, CD163+, and MARCO+ Macrophages as Prognostic Biomarkers in Patients With Treatment-Naïve Gastroesophageal Adenocarcinoma
- 2020
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Ingår i: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Despite improvements in surgical methodologies and perioperative chemo- and radiotherapy, the prognosis for patients with esophageal and gastric cancer remains poor. Hence, there is a great need to identify complementary biomarkers for improved treatment stratification. Tumor-infiltrating immune cells have been shown to impact on outcome in many types of cancer, including gastroesophageal cancer. The aim of this present study was to examine the prognostic value of tumor-infiltrating macrophages in gastroesophageal adenocarcinoma. Methods: The density of CD68+, CD163+, and MARCO+ macrophages was assessed by immunohistochemistry on tissue microarrays with primary tumors from a consecutive, retrospective cohort of 174 patients with treatment-naïve gastroesophageal adenocarcinoma. Total densities and infiltration in tumor nest (TN) were denoted as none/sparse (0), intermediate (1), or high (2). The impact on overall survival (OS) was examined by Kaplan–Meier analysis, log-rank test, and Cox proportional hazards modeling. Results: Increased infiltration of both CD68+ and CD163+, but not MARCO+, macrophages in TN was significantly associated with a stepwise reduced survival. Median OS for patients with none/sparse, intermediate, and high CD68+ TN infiltration was 4.4, 2.6, and 1.0 years, respectively. Median OS for patients with none/sparse, intermediate, and high CD163+ TN infiltration was 4.4, 2.2, and 1.1 years, respectively. High infiltration of CD68+ macrophages remained an independent prognostic factor in adjusted analysis (hazard ratio = 1.61, 95% confidence interval = 1.02–2.55, and p = 0.041). Conclusion: Infiltration of CD68+ and CD163+, but not MARCO+, macrophages is prognostic for OS in gastroesophageal adenocarcinoma. The relevance of this finding in clinical practice remains to be elucidated.
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| 2. |
- Mezheyeuski, Artur, et al.
(författare)
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An immune score reflecting pro- and anti-tumoural balance of tumour microenvironment has major prognostic impact and predicts immunotherapy response in solid cancers
- 2023
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 88
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cancer immunity is based on the interaction of a multitude of cells in the spatial context of the tumour tissue. Clinically relevant immune signatures are therefore anticipated to fundamentally improve the accuracy in predicting disease progression.Methods: Through a multiplex in situ analysis we evaluated 15 immune cell classes in 1481 tumour samples. Single-cell and bulk RNAseq data sets were used for functional analysis and validation of prognostic and predictive associations.Findings: By combining the prognostic information of anti-tumoural CD8+ lymphocytes and tumour supportive CD68+CD163+ macrophages in colorectal cancer we generated a signature of immune activation (SIA). The prognostic impact of SIA was independent of conventional parameters and comparable with the state-of-art immune score. The SIA was also associated with patient survival in oesophageal adenocarcinoma, bladder cancer, lung adenocarcinoma and melanoma, but not in endometrial, ovarian and squamous cell lung carcinoma. We identified CD68+CD163+ macrophages as the major producers of complement C1q, which could serve as a surrogate marker of this macrophage subset. Consequently, the RNA-based version of SIA (ratio of CD8A to C1QA) was predictive for survival in independent RNAseq data sets from these six cancer types. Finally, the CD8A/C1QA mRNA ratio was also predictive for the response to checkpoint inhibitor therapy.Interpretation: Our findings extend current concepts to procure prognostic information from the tumour immune microenvironment and provide an immune activation signature with high clinical potential in common human cancer types.
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| 3. |
- Mezheyeuski, Artur, et al.
(författare)
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The ratio of CD8+ lymphocytes to CD68+CD163+ macrophages is prognostic in immunogenic tumors and predicts immunotherapy response
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Immune cells in the microenvironment shape tumor development and progression. Through in situ analyses we assessed 15 immune cell classes in 352 colorectal cancers and identified a simpleprognostic signature based on the ratio of anti-tumoral CD8+ lymphocytes to tumor-supportiveCD68+CD163+ macrophages in the tumor microenvironment. The prognostic ability of this signature was superior to the state-of-art immune score and was also demonstrated in four other tumor types. Single-cell analyses identified these CD68+CD163+ macrophages as the source of complement C1q, and the ratio of CD8A to C1QA gene expression levels in bulk RNA predicted survival in five tumor types. In single cell analyses, RNA-based versions of the signature also predicted response to checkpoint inhibitor therapy. This supports broad clinical applicability of immune scores considering CD68+CD163+ macrophages as prognostic and predictive biomarkers in common cancers.
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| 4. |
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| 5. |
- Svensson, Maria C., et al.
(författare)
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Expression of PD-L1 and PD-1 in chemoradiotherapy-Naïve esophageal and gastric adenocarcinoma : Relationship with mismatch repair status and survival
- 2019
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Ingår i: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 9:MAR
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Tidskriftsartikel (refereegranskat)abstract
- Background: The outlook for patients with esophageal and gastric (EG) cancer remains poor. Hence, there is a compelling need to identify novel treatment strategies and complementary biomarkers. Programmed death ligand 1 (PD-L1) and mismatch repair deficiency (dMMR) are putative biomarkers of response to immune-checkpoint blockade, but their prognostic value and interrelationship in EG cancer have been sparsely investigated. Methods: Immunohistochemical expression of PD-L1 on tumour cells (TC) and tumour-infiltrating immune cells (TIC), and of PD-1 (programmed death receptor 1) on TIC was assessed using tissue microarrays with primary tumours and a subset of paired lymph node metastases from a consecutive, retrospective cohort of 174 patients with chemoradiotherapy-naïve EG adenocarcinoma. MMR proteins MLH1, PMS2, MSH2, and MSH6 were assessed by immunohistochemistry. The total number (intratumoural, tumour-adjacent, and stromal) of CD8+ T cells in each core was calculated by automated analysis. Results: High PD-L1 expression on both TC and TIC, but not PD-1 expression, was significantly associated with dMMR. PD-L1 expression on TIC was significantly higher in lymph node metastases than in primary tumours. High expression of PD-L1 or PD-1 on TIC was significantly associated with a prolonged survival, the former independently of established prognostic factors. A significant stepwise positive association was found between CD8 + T cells and categories of PD-L1 expression on TIC. Conclusion: PD-L1 expression on TIC is higher in lymph node metastases compared to primary tumours, correlates with dMMR, and is an independent factor of prolonged survival in patients with chemoradiotherapy-naïve EG adenocarcinoma. These findings suggest that PD-L1 expression on TIC may be a useful biomarker for identifying patients who may not need additional chemo-or chemoradiotherapy, and who may benefit from PD-1/PD-L1 immune-checkpoint blockade.
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| 6. |
- Svensson, Maria C, et al.
(författare)
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High infiltration of CD68+/CD163- macrophages is an adverse prognostic factor after neoadjuvant chemotherapy in esophageal and gastric adenocarcinoma
- 2022
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Ingår i: Journal of Innate Immunity. - : S. Karger AG. - 1662-811X .- 1662-8128. ; 14:6, s. 615-628
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Tidskriftsartikel (refereegranskat)abstract
- Tumor-associated macrophages (TAMs) have emerged as key players in tumor immunology but demonstrate a continuum of functional states being either tumor suppressive or promoting. Moreover, chemotherapeutic agents have been shown to alter the tumor microenvironment. Perioperative chemotherapy is a standard treatment option for resectable esophageal and gastric (EG) adenocarcinoma. The aim of this study was to investigate the influence of neoadjuvant chemotherapy (NAC) on TAMs to improve the prognostication and treatment course for these patients. The study cohort comprised 148 patients, all of whom were diagnosed with resectable EG adenocarcinoma and treated with NAC. Immunohistochemistry was applied to assess the total infiltration and infiltration into tumor nests (TN) of CD68+/CD163−, CD68+/CD163+, and MARCO+ TAMs, on paired biopsies from primary tumors (PT) pre-NAC, and resected PT and lymph node metastases post-NAC. In pre-NAC specimens, high CD68+/CD163+ infiltration into TN was an unfavorable prognostic factor. No association was found between TAM density in PT pre-NAC and histopathological regression. The density of CD68+/CD163+ TAMs was increased in PT post-NAC, while the density of MARCO+ TAMs was decreased. CD68+/CD163− TAM density was not altered. In post-NAC specimens, higher total as well as TN infiltration of CD68+/CD163−TAMs were adverse prognostic factors. In conclusion, these results suggest that NAC may alter certain TAM subsets in EG adenocarcinoma, along with their functional properties and thus their prognostic value.
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| 7. |
- Svensson, Maria Christina, et al.
(författare)
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T cells, B cells, and PD-L1 expression in esophageal and gastric adenocarcinoma before and after neoadjuvant chemotherapy : relationship with histopathological response and survival
- 2021
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Ingår i: OncoImmunology. - 2162-4011. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Perioperative chemotherapy enhances the survival rates for patients with esophageal and gastric (EG) adenocarcinoma, but not all patients benefit from this additional treatment. Chemotherapeutic agents have been demonstrated to alter the immune cell (IC) composition in the tumor microenvironment. Hence, there is a rationale to investigate the influence of neoadjuvant chemotherapy (NAC) on different IC subsets, to better understand and compare their utility as complementary prognostic or predictive biomarkers in a clinically relevant context. The density of T cells (CD8+ and FoxP3+), B cells (CD20+) and the expression of PD-L1 on ICs and tumor cells (TC) was assessed by immunohistochemistry on paired biopsies from primary tumors (PT) pre-NAC, and resected PT and lymph node metastases post-NAC. The cohort encompasses 148 patients with resectable EG adenocarcinoma, all of whom received NAC. The density of CD8+ cells was decreased and the density of FoxP3+ cells and CD20+ cells was increased in PT post-NAC. PD-L1 expression was not altered following NAC. In pre-NAC specimens, high FoxP3+ density and high PD-L1 expression on ICs were favorable prognostic factors, whereas high CD8+ density was an unfavorable prognostic factor. In post-NAC specimens, however, high FoxP3+ density was an unfavorable prognostic factor, and high PD-L1 expression on TC was associated with a shorter survival. There were no significant associations between IC density or PD-L1 expression in PT pre-NAC and histopathological regression. These findings propose that NAC might alter the density and prognostic impact of some IC subsets in EG adenocarcinoma.
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| 8. |
- Svensson, Maria C, et al.
(författare)
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The integrative clinical impact of tumor-infiltrating T lymphocytes and NK cells in relation to B lymphocyte and plasma cell density in esophageal and gastric adenocarcinoma
- 2017
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Ingår i: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 8:42, s. 72108-72126
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Tidskriftsartikel (refereegranskat)abstract
- Background: Several studies have demonstrated a prognostic impact of tumor-infiltrating T lymphocytes and natural killer (NK) cells in esophageal and gastric adenocarcinoma, but whether these associations differ by the density of tumor-infiltrating immune cells of the B cell lineage remains largely unknown. Results: High infiltration of any T and NK lymphocytes investigated was in general associated with a favorable prognosis, but the strongest beneficial prognostic impact was seen in combination with high B lymphocyte infiltration. These findings were most evident in gastric cancer, where significant interactions in relation to OS were observed for CD3(+), CD8(+) and FoxP3(+) with CD20(+) cells (p(interaction) = 0.012, 0.009 and 0.007, respectively) and for FoxP3(+) with IGKC(+) cells (p(interaction) = 0.034). In esophageal tumors, there was only a significant interaction for CD3(+) and CD20 (+) cells (p(interaction) = 0.028). Methods: Immunohistochemistry and automated image analysis was applied to assess the density of T lymphocytes (CD3(+), CD8(+), FoxP3(+)) and NK cells (NKp46(+)) in chemoradiotherapy-naive tumors from a consecutive cohort of 174 patients with resected esophageal or gastric adenocarcinoma. The density of B lymphocytes (CD20(+)) and plasma cells (IGKC(+)) had been assessed previously. Kaplan-Meier analysis and Cox proportional hazard's modelling was applied to examine the impact of the investigated markers on time to recurrence (TTR) and overall survival (OS). Conclusions: These data support that the antitumoral effects of tumor-infiltrating T lymphocytes in esophageal and gastric adenocarcinoma may be largely dependent on a functional interplay between T and B lymphocytes or plasma cells.
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| 9. |
- BORG, DAVID, et al.
(författare)
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Expression of IFITM1 as a prognostic biomarker in resected gastric and esophageal adenocarcinoma
- 2016
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Ingår i: Biomarker research. - : Springer Science and Business Media LLC. - 2050-7771. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There is an increasing amount of reports on IFITM1 (interferon-inducible transmembrane protein 1) in various malignancies. The aim of this study was to examine the expression of IFITM1 and its prognostic significance in gastroesophageal adenocarcinoma.METHODS: Tissue samples were obtained from a consecutive cohort of 174 patients surgically treated between 2006 and 2010 for gastroesophageal (gastric, gastroesophageal junction and esophageal) adenocarcinoma, not subjected to neoadjuvant therapy. Expression of IFITM1 was examined using immunohistochemistry on tissue microarrays of primary tumors and paired samples of adjacent normal epithelium, intestinal metaplasia and lymph node metastases.RESULTS: Expression of IFITM1 was significantly elevated in primary tumors and lymph node metastases compared to adjacent normal epithelium and intestinal metaplasia, regardless of tumor location. Overexpression of IFITM1 was associated with M0-disease (no distant metastases). In gastric cancer IFITM1 expression was significantly associated with improved TTR (time to recurrence) in Kaplan-Meier analysis and Cox regression, both in the unadjusted analysis (HR 0.33, 95 % CI 0.12-0.88) and in the adjusted analysis (HR 0.32, 95 % CI 0.12-0.87) but there was no significant impact on OS (overall survival). In esophageal adenocarcinoma expression of IFITM1 had no impact on TTR or OS in Kaplan-Meier-analyses, but in the adjusted Cox regression IFITM1 expression had a negative impact on both TTR (HR 3.05, 95 % CI 1.09-8.53) and OS (HR 2.71, 95 % CI 1.11-6.67).CONCLUSIONS: IFITM1 was overexpressed in gastroesophageal adenocarcinoma and associated with M0-disease. In gastric cancer IFITM1 expression had a positive impact on TTR but in esophageal cancer it seemed to have an adverse impact on survival. The reason for the diverging prognostic impact of IFITM1 in esophageal and gastric cancer is unclear and warrants further studies.
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| 10. |
- Borg, David, et al.
(författare)
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Expression of podocalyxin-like protein is an independent prognostic biomarker in resected esophageal and gastric adenocarcinoma
- 2016
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Ingår i: BMC Clinical Pathology. - : Springer Science and Business Media LLC. - 1472-6890. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Podocalyxin-like protein (PODXL) is a cell surface transmembrane glycoprotein, the expression of which has been associated with poor prognosis in a range of malignancies. The aim of this study was to investigate the impact of PODXL expression on survival in esophageal and gastric adenocarcinoma. Methods: The study cohort consists of a consecutive series of 174 patients with esophageal (including the gastroesophageal junction) or gastric adenocarcinoma, surgically treated between 2006 and 2010 and not subjected to neoadjuvant treatment. Immunohistochemical expression of PODXL was assessed in tissue microarrays with cores from primary tumors, lymph node metastases, intestinal metaplasia and adjacent normal epithelium. Survival analyses were performed on patients with no distant metastases and no macroscopic residual tumor. Results: In the majority of cases, expression of PODXL was significantly higher in cancer cells compared to normal epithelial cells and was significantly associated with lymph node metastases and high grade tumors. In esophageal adenocarcinoma, Kaplan-Meier analyses revealed that patients with PODXL negative tumors had a superior time to recurrence (TTR) and overall survival (OS) compared to patients with PODXL positive tumors. In gastric adenocarcinoma, patients with PODXL negative tumors had a superior TTR and a trend towards an improved OS. In esophageal and gastric adenocarcinoma combined, the prognostic significance of PODXL expression on TTR was confirmed in unadjusted Cox regression analysis (HR = 5.36, 95 % CI 1.68-17.06, p = 0.005) and remained significant in the adjusted model (HR = 3.39, 95 % CI 1.01-11.35, p = 0.048). Moreover, the impact of PODXL expression on OS was also confirmed in unadjusted analysis (HR = 2.52, 95 % CI 1.31-4.85, p = 0.006) and remained significant in the adjusted model (HR = 2.03, 95 % CI 1.04-3.98, p = 0.039). Conclusions: In esophageal and gastric adenocarcinoma, PODXL expression is an independent prognostic biomarker for reduced time to recurrence and poor overall survival. This is the first report on the prognostic role of PODXL in esophageal adenocarcinoma and validates recent findings in gastric cancer.
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