| 1. |
- Winerdal, Malin E., et al.
(författare)
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Urinary Bladder Cancer Tregs Suppress MMP2 and Potentially Regulate Invasiveness
- 2018
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Ingår i: CANCER IMMUNOLOGY RESEARCH. - : American Association for Cancer Research (AACR). - 2326-6066 .- 2326-6074. ; 6:5, s. 528-538
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Tidskriftsartikel (refereegranskat)abstract
- Regulatory T cells (Treg) have long been considered one-sided suppressors of antitumor immune responses and hence associated with poor patient outcome in cancer. However, evidence is mounting of a paradoxical positive prognostic effect of Tregs on certain malignancies, including urinary bladder cancer (UBC). This discrepancy has partly been attributed to the shear misidentification of Tregs, but also to the inflammatory profile of the tumor. Our aim was to determine whether tumor-infiltrating Forkhead box P3+ (FOXP3+) cells confer a stable Treg phenotype and to investigate putative beneficial Treg functions, focusing on tumor-promoting inflammatory pathways in UBC. Patients (n = 52) with suspected UBC were prospectively included. We show, by using a broad range of analytical approaches, that tumor-infiltrating CD4+FOXP3+ T cells in UBC phenotypically, functionally, and epigenetically represent a true Treg population. At the invasive front of UBC tumors, we found an inverse relationship between Treg frequency and expression of matrix metalloproteinase 2 (MMP2), a key proinvasive factor induced by tumor-promoting inflammation. Correspondingly, a significant, dose-dependent Treg-mediated downregulation of MMP2 protein and mRNA expression was observed in both macrophages and UBC cells. Also, we found that Treg frequency specifically at the invasive front positively correlated with survival. Thus, we identify Treg-mediated suppression of MMP2 in the tumor microenvironment as a mechanism explaining the paradoxical positive prognostic impact of tumor-infiltrating Tregs in UBC.
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| 2. |
- Zirakzadeh, A. Ali, et al.
(författare)
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Doxorubicin enhances the capacity of B cells to activate T cells in urothelial urinary bladder cancer
- 2017
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Ingår i: Clinical Immunology. - : Elsevier BV. - 1521-6616 .- 1521-7035. ; 176, s. 63-70
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is currently treated by a combination of therapies, including chemotherapy which is believed to suppress the immune system. Combination of immunotherapy and chemotherapy correlates with improved survival but needs careful planning in order to achieve a synergistic effect. In this study, we have demonstrated that doxorubicin treatment of B cells resulted in increased expression of CD86 and concordantly increased CD4(+) T cell activation in the presence of superantigen, an effect that was inhibited by the addition of a CD86 blocking antibody. Furthermore, doxorubicin resulted in decreased expression of the anti-inflammatory cytokines IL-10 and TNF-alpha. Finally, B cells from urinary bladder cancer patients, treated with a neoadjuvant regiment containing doxorubicin, displayed increased CD86-expression. We conclude that doxorubicin induces CD86 expression on B cells and hence enhances their antigen-presenting ability in vitro, a finding verified in patients. Development of tailored time and dose schedules may increase the effectiveness of combining chemotherapy and immunotherapy.
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| 3. |
- Zirakzadeh, A. Ali, et al.
(författare)
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Tumour-associated B cells in urothelial urinary bladder cancer
- 2020
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Ingår i: Scandinavian Journal of Immunology. - : Wiley-Blackwell. - 0300-9475 .- 1365-3083. ; 91:2
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Tidskriftsartikel (refereegranskat)abstract
- Tumour infiltrating B cells and CD38+ plasma cells have been correlated with survival in different malignancies but their role in urinary bladder cancer is unclear. IL-10 is a multifunctional cytokine with both anti-inflammatory and immunostimulatory properties, that can be released by regulatory B cells (Bregs). We have stained paraffin-embedded tumour sections from 31 patients with invasive urothelial urinary bladder cancer with respect to CD20+ B cells, CD38+ cells, IL-10-expressing cells, IgG, C1q and C3a and analysed the impact of these markers on survival. Interestingly, we observe tumour-associated CD20+ B cells forming follicle-like structures in tumours of some patients. We demonstrate that follicle-like structures, tumour-associated CD38+ cells, IL-10 produced by non-B cells, tumour infiltrating IgG and activation of the complement system, may associate to longer survival of urinary bladder cancer patients. IL-10 expression by tumour-associated Bregs may instead negatively affect prognosis. More research is needed to fully understand the role of B cells and IL-10 in urinary bladder cancer.
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