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  • Allaoui, Roni, et al. (författare)
  • Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers
  • 2016
  • Ingår i: Nature Communications. - Nature Publishing Group. - 2041-1723. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • Triple-negative (TN) breast cancers (ER â ' PR â ' HER2 â ') are highly metastatic and associated with poor prognosis. Within this subtype, invasive, stroma-rich tumours with infiltration of inflammatory cells are even more aggressive. The effect of myeloid cells on reactive stroma formation in TN breast cancer is largely unknown. Here, we show that primary human monocytes have a survival advantage, proliferate in vivo and develop into immunosuppressive myeloid cells expressing the myeloid-derived suppressor cell marker S100A9 only in a TN breast cancer environment. This results in activation of cancer-associated fibroblasts and expression of CXCL16, which we show to be a monocyte chemoattractant. We propose that this migratory feedback loop amplifies the formation of a reactive stroma, contributing to the aggressive phenotype of TN breast tumours. These insights could help select more suitable therapies targeting the stromal component of these tumours, and could aid prediction of drug resistance.
  • Allaoui, Roni, et al. (författare)
  • Infiltration of γδ T cells, IL-17 + T cells and FoxP3 + T cells in human breast cancer
  • 2017
  • Ingår i: Cancer Biomarkers. - IOS Press. - 1574-0153. ; 20:4, s. 395-409
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Tumor-infiltrating lymphocytes (TILs) have a strong prognostic value in various forms of cancers. These data often refer to use of the pan-T cell marker CD3, or the cytotoxic T lymphocyte marker CD8α. However, T cells are a heterogeneous group of cells with a wide array of effector mechanisms ranging from immunosuppression to cytotoxicity. OBJECTIVE: In this study we have investigated the prognostic effects of some unconventional T cell subtypes in breast cancer; γδ T cells, IL-17+ T cells and FoxP3+ T cells (Tregs) in relation to the conventional CD3 and CD8α T cell markers. METHODS: This was done using immunohistochemistry on a human breast cancer tissue microarray consisting of 498 consecutive cases of primary breast cancer. RESULTS: Infiltration of γδ T cells and T cell infiltration in general (CD3), correlated with a good prognosis, while Treg infiltration with a worse. Infiltration of γδ T cells was associated with a significantly improved clinical outcome in all breast cancer subtypes except triple negative tumors. Only infiltration of either CD3+ or CD8α+ cells was independently associated with better prognosis for all breast cancer patients. CONCLUSIONS: This study sheds further light on the prognostic impact of various T cell subtypes in breast cancer.
  • Backman, Max, et al. (författare)
  • Characterization of Patterns of Immune Cell Infiltration in NSCLC
  • ????
  • Ingår i: Journal of Thoracic Oncology. - Elsevier. - 1556-0864.
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Tumor infiltrating immune cells are key elements of the tumor microenvironment and mediate the antitumor effects of immunotherapy. The aim of the study was to characterize the patterns of immune cell infiltration in NSCLC in relation to tumor mutations and clinicopathologic parameters. Methods: Lymphocytes (CD3+, CD4+, CD8+, CD20+, FOXP3+, CD45RO+), macrophages (CD163+), plasma cells (CD138+), natural killer (NK) cells (NKp46+), and programmed death-ligand 1 (PD-L1+) were annotated on a tissue microarray including 357 patients who had undergone operations for NSCLC. Somatic mutations and tumor mutational burden were analyzed by targeted sequencing for 82 genes, and transcriptomic immune patterns were established in 197 patients on the basis of RNAseq data. Results: We identified somatic mutations (TP53, NF1, KEAP1, CSMD3, LRP1B) that correlated with specific immune cell infiltrates. Hierarchical clustering revealed four immune classes: with (1) high immune cell infiltration (“inflamed”), (2) low immune cell infiltration (“desert”), (3) a mixed phenotype, and (4) a new phenotype with an overall muted inflammatory cell pattern but with an imprint of NK and plasma cells. This latter class exhibited low expression of immune response-related genes (e.g., CXCL9, GZMB, INFG, TGFB1) but was linked to better survival and, therefore, designated “oasis.” Otherwise, the four immune classes were not related to the presence of specific mutations (EGFR, KRAS, TP53) or histologic subtypes. Importantly, the identified immune classes on the basis of tissue staining could not be translated into RNA expression signatures extracted from crude NSCLC tissue. Conclusions: We presented a compartment-specific immune cell analysis in the context of the molecular and clinical background of NSCLC and identified the novel immune class oasis. The immune classification helps to better define the immunogenic potency of NSCLC in the era of immunotherapy.
  • Backman, Max, et al. (författare)
  • Extending the immune phenotypes of lung cancer: Oasis in the desert
  • ????
  • Annan publikation (övrigt vetenskapligt)abstract
    • <p>Introduction: Tumor infiltrating immune cells are key elements of the tumor microenvironment and mediate the anti-tumor effects of immunotherapy. The aim of the study was to characterize patterns of immune cell infiltration in non-small cell lung cancer (NSCLC) in relation to tumor mutations and clinicopathological parameters. </p><p>Methods: Lymphocytes (CD4+, CD8+, CD20+, FOXP3+, CD45RO+), macrophages (CD163+), plasma cells (CD138+), NK cells (NKp46+) and PD-L1+ were annotated on a tissue microarray including 357 operated NSCLC cases. Somatic mutations and tumor mutational burden were analyzed by targeted sequencing for 82 genes, and transcriptomic immune patterns were established in 197 patients based on RNAseq data. </p><p>Results: We identified somatic mutations (TP53, NF1, KEAP1, CSMD3, LRP1B) that correlated with specific immune cell infiltrates. Hierarchical clustering revealed four immune classes: with (1) high immune cell infiltration (“inflamed”), (2) low immune cell infiltration (“desert”), (3) a mixed phenotype, and (4) a new phenotype with an overall muted inflammatory cell pattern but with an imprint of NK and plasma cells. This latter class exhibited low expression of immune response-related genes (e.g. CXCL9, GZMB, INFG, TGFB1), but was linked to better survival and therefore designated “oasis”. Otherwise, the four immune classes were not related to the presence of specific mutations (EGFR, KRAS, TP53) or histologic subtypes. </p><p>Conclusion: We present a compartment-specific immune cell analysis in the context of the molecular and clinical background of NSCLC and identified the novel immune class “oasis”. The immune classification helps to better define the immunogenic potency of NSCLC in the era of immunotherapy. </p>
  • Bergenfelz, Caroline, et al. (författare)
  • S100A9 expressed in ER(-)PgR(-) breast cancers induces inflammatory cytokines and is associated with an impaired overall survival.
  • 2015
  • Ingår i: British Journal of Cancer. - Nature Publishing Group. - 1532-1827. ; 113:8, s. 1234-1243
  • Tidskriftsartikel (refereegranskat)abstract
    • Breast cancer is the most common cancer form among women today. Depending on hormone receptor status, breast cancers are divided into different subtypes with vastly varying prognosis. S100A9 is a calcium-binding protein that is associated with inflammation and expressed not only in myeloid cells but also in some tumours. The role for S100A9 in the malignant cells is not well characterised; however, previous studies have shown that the protein could have important immune-modulating properties.
  • Bergenfelz, Caroline, et al. (författare)
  • Wnt5a induces a tolerogenic phenotype of macrophages in sepsis and breast cancer patients.
  • 2012
  • Ingår i: Journal of immunology (Baltimore, Md. : 1950). - American Association of Immunologists. - 1550-6606. ; 188:11, s. 5448-5458
  • Tidskriftsartikel (refereegranskat)abstract
    • A well-orchestrated inflammatory reaction involves the induction of effector functions and, at a later stage, an active downregulation of this potentially harmful process. In this study we show that under proinflammatory conditions the noncanonical Wnt protein, Wnt5a, induces immunosuppressive macrophages. The suppressive phenotype induced by Wnt5a is associated with induction of IL-10 and inhibition of the classical TLR4-NF-κB signaling. Interestingly, this phenotype closely resembles that observed in reprogrammed monocytes in sepsis patients. The Wnt5a-induced feedback inhibition is active both during in vitro LPS stimulation of macrophages and in patients with sepsis caused by LPS-containing, Gram-negative bacteria. Furthermore, using breast cancer patient tissue microarrays, we find a strong correlation between the expression of Wnt5a in malignant epithelial cells and the frequency of CD163(+) anti-inflammatory tumor-associated macrophages. In conclusion, our data point out Wnt5a as a potential target for an efficient therapeutic modality in severe human diseases as diverse as sepsis and malignancy.
  • Bergenfelz, Caroline, et al. (författare)
  • Wnt5a inhibits human monocyte derived myeloid dendritic cell generation.
  • 2013
  • Ingår i: Scandinavian Journal of Immunology. - Wiley-Blackwell. - 1365-3083. ; 78:2, s. 194-204
  • Tidskriftsartikel (refereegranskat)abstract
    • Wnt5a is a non-canonical Wnt protein that is expressed at elevated levels in inflammatory conditions. Its role in inflammation remains unclear, although it is known that Wnt5a is expressed at a higher level in monocyte-derived myeloid dendritic cells (Mo-mDCs) than in monocytes and macrophages. The function of Wnt5a in dendritic cells (DCs) remains relatively unexplored. Here, we found that under Mo-mDC culture conditions, Wnt5a inhibited the generation of CD14(+/low) Mo-mDCs while promoting the generation of CD14(+/++) CD16(+) monocytes. We could further show that stimulation of monocytes with rWnt5a induced a rapid IL-6 production and that the rWnt5a treated Mo-mDC differentiation was restored upon blocking of IL-6. Also conditioned media from Wnt5a stimulated human breast cancer cells producing IL-6, specifically inhibited Mo-mDC differentiation. These observations are strengthened by our finding that patients with sepsis, a disease involving elevated Wnt5a and IL-6 levels, also showed a significant increase in the CD14(+) CD16(++) /CD14(+/++) CD16(+) monocyte populations, which was accompanied by a significant decrease in circulating mDCs. We finally show that under typical Mo-mDC culture conditions, monocytes isolated from sepsis patients as compared to healthy controls, preferentially differentiated into CD14(+/++) HLA-DR(++) cells. We suggest that Wnt5a is a possible candidate mediator for the CD14(+/++) CD16(+) monocyte accumulation seen in infectious disease and cancer patients. This article is protected by copyright. All rights reserved.
  • Berntsson, Jonna, et al. (författare)
  • Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in colorectal cancer : Relationship with sidedness and prognosis
  • 2018
  • Ingår i: OncoImmunology. - Landes Bioscience. - 2162-4011. ; 7:8
  • Tidskriftsartikel (refereegranskat)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.
  • Berntsson, Jonna, et al. (författare)
  • Pre-diagnostic anthropometry, sex, and risk of colorectal cancer according to tumor immune cell composition
  • 2019
  • Ingår i: OncoImmunology. - Landes Bioscience. - 2162-4011. ; 8:12
  • Tidskriftsartikel (refereegranskat)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.
  • Berntsson, Jonna, et al. (författare)
  • The clinical impact of tumour-infiltrating lymphocytes in colorectal cancer differs by anatomical subsite : A cohort study
  • 2017
  • Ingår i: International Journal of Cancer. - John Wiley and Sons Inc.. - 0020-7136. ; 141:8, s. 1654-1666
  • Tidskriftsartikel (refereegranskat)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 reference to the anatomical subsite of the primary tumour. The density of CD3+, CD8+ and FoxP3+ tumour-infiltrating T cells 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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