Supplementary figure 7 from Anti–PD-1 Efficacy in Patients with Metastatic Urothelial Cancer Associates with Intratumoral Juxtaposition of T Helper-Type 1 and CD8<sup>+</sup> T cells
Maud RijndersHayri E. BalcıoğluDebbie RobbrechtAstrid A.M. OostvogelsRebecca WijersMaureen J.B. AartsPaul HambergGeert J.L.H. van LeendersJ. Alberto Nakauma-GonzálezJens VoortmanHans M. WestgeestJoost L. BoormansRonald de WitMartijn P. LolkemaAstrid A.M. van der VeldtReno Debets
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<p>CD20+ B-cells are present in immune cell niches in lesions of responders upon anti-PD1 treatment</p>Keywords:
Urothelial cancer
Cancer Immunotherapy
Immune checkpoint
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In this report we describe a system for the generation of functional, class I MHC-restricted, T-T hybridomas. The BW5147 cell line was transfected with the CD8 gene. BW5147 transfectants were obtained that stably expressed CD8 and this expression was maintained after somatic cell hybridization with activated T lymphocytes. To determine whether the stable expression of CD8 would facilitate the generation of class I MHC-specific T-T hybridomas, the transfected cells were fused with alloreactive T cells and the resultant hybrids were screened for their ability to produce lymphokines in response to antigenic stimulation. Somatic cell hybridizations with BW5147-CD8 transfectants give rise to a much higher frequency of class I MHC-specific T-T hybridomas relative to parallel fusions with BW5147. To determine whether the BW5147-CD8 transfectants would also support the generation of Ag-specific, class I MHC-restricted T-T hybridomas, they were fused with OVA-specific CTL. Several T-T hybrid clones were identified that produced lymphokines after stimulation with a transfected APC that was synthesizing OVA, or with a tryptic digest of OVA in the presence of syngeneic APC. The stimulation by Ag was MHC-restricted and mapped to the Kb molecule. An anti-CD8 mAb inhibited the stimulation of these hybridomas by Ag plus APC, whereas their stimulation by mitogen was unaffected. Cytolytic activity was not detected when several of the OVA-specific or alloreactive hybridomas were tested for their ability to kill target cells bearing the appropriate Ag. These results demonstrate that the BW5147-CD8 transfectants allow the generation of class I MHC-restricted T-T hybridomas. The potential utility of this system is discussed.
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Two reports in this issue describe a nomogram for predicting survival and a landmark analysis demonstrating the relation between 6‐month and 9‐month progression‐free status and overall survival in patients with metastatic urothelial cancer. These 2 important tools will be used to improve future clinical trial design in patients with advanced urothelial cancer.
Urothelial cancer
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Clinical study design
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To explore the role of IL-22 on the recovery and function of thymus from graft-versus host disease (GVHD) mice after allogeneic bone marrow transplantation (allo-BMT).GVHD model was established by using of recipient male BALB/c and donor male C57BL/6 mice(6-8 W) respectively. The mice were divided into normal group, GVHD with IL-22 group (BS+IL-22) and without IL-22 group (BS+PBS). Numbers of thymus cells were detected at different time points. The ratio of T cell subsets from thymus was observed by flow cytometry. Percentages of IFN-γ-producing and IL-17-producing CD4+ T or CD8+ T cells were detected.The total number of thymus cells in BS+IL-22 mice [(14.6±5.1)×10⁴] was significantly higher than that in BS+PBS mice [(6.2±2.9)×10⁴] at 14 days after allo-BMT. Thymus cells in BS+IL-22 mice expanded continuously and reached at the level of normal mice, which were still higher than that in BS+PBS group. Although there was no impact on the ratio of mature CD4+ and CD8+ T cell from thymus, the percentage of immature CD4+CD8+ T cell increased obviously in mice treated with IL-22. Percentages of IFN-γ+CD4+ T cell [Th1:(2.42±0.75)%] and IFN-γ+CD8+ T cell [Tc1:(5.44±0.47)%] were up-regulated by IL-22 treatment, whereas no changes were detected in IL-17+CD4+ T cell (Th17) and IL-17+CD8+ T cell (Tc17).IL-22 accelerates the progress of thymus recovery, and increases the IFN-γ-producing ability of thymus CD4+ and CD8+ T cells from GVHD mice.
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Background. The in vivo effects of immunosuppressants on T cells are classically determined using animal models of organ transplantation. These methods are technically difficult and time consuming. A simple in vivo method is needed for screening new immunosuppressants. Methods. Donor mouse spleen cells were labeled with a fluorescent dye, carboxy-fluorescein diacetate succinimidyl ester (CFSE), and then injected into the blood of recipient severe combined immunodeficiency mice. Three days after the injection, spleen cells of the recipient mice were isolated and the proliferating alloreactive T cells were analyzed by flow cytometry. Results. In control recipient mice, 50% of the T cells were proliferating, consisting of both CD4+ and CD8+ T cells. In cyclosporine- or FK506-treated mice, T-cell proliferation was suppressed in the CD4 subset but not in the CD8 subset. On the contrary, T-cell proliferation was significantly reduced in the CD8 subset but not in the CD4 subset in recipient mice treated with rapamycin. Conclusion. The present mouse model using carboxy-fluorescein diacetate succinimidyl ester labeling is simple and fast. It is useful for screening new immunosuppressants and for examining the effect on T-cell subsets.
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Objecfive To study T cell subsets distribution in peripheral blood from patients with ankylosing spondylitis(AS)and the role of cell immunity in AS.Methods 30 patients with untreated active phase AS and 30 healthy volunteers were enrolled.The expression of CD4+ and CD8+ T cell subsets were evaluated by flow eytome try.The correlation among T cell subsets and Bath AS function index(BASFI).Bath AS measurement index(BASMI),course of disease,age,ESR,hyper-sensitive C-reactive protein (hs-CRP) were analyzed.Results The level of CD4+ T cell and CD4/CD8+ratio were significantly lower than that of healthy volunteers[(29.24±9.22)% vs.(40.09±6.86) %,(0.96±0.49 ) vs.(1.70±0.67 ),P ＜ 0.01 ],and CD8+ T cell were significantly higher than that of healthy volunteers [(32.91±6.86) % vs.(25.60± 5.97 ) %,P ＜ 0.01 ].The level of CD4+ T cell subsets in peripheral blood of AS patients was negatively correlated with BASMI (r =-0.479,P ＜ 0.01 ),and CD8+ T cell subsets were positively correlated with ESR,hs-CRP,BASFI and BASMI ( r = 0.373,0.430,0.462,0.530,P ＜0.05 ).The ratio of CD4+/CD8+ was negatively correlated with hs-CRP,BASFI and BASMI (r = -0.465,- 0.473,- 0.426,P ＜ 0.05 ).CD4+,CD8+,ratio of CD4/CD8 were not significantly correlated with age and course of disease in patients with AS.Conclusion T cell subsets are significantly abnormal in peripheral blood of patients with AS,and the imbalance degree of T cell is correlated with severity and activity of AS,suggesting that T cell subsets imbalance plays an important role in the pathologensis of AS.
Key words:
Ankylosing spondylitis; T cell subsets; CD4+; CD8+
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Spondylitis
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Abstract The immunology of vertical HIV transmission differs from that of adult infection in that the immune system of the infant is not fully matured, and the factors that influence the functionality of CD8+ T cell responses against HIV in children remain largely undefined. We have investigated CD8+ T cell responses in 65 pediatric subjects with vertically acquired HIV-1 infection. Vigorous, broad, and Ag dose-driven CD8+ T cell responses against HIV Ags were frequently observed in children who were older than 3 years of age and maintained CD4+ T cell counts >400 cells/μl. In contrast, younger age or a CD4+ T cell count <400 cells/μl was associated with poor CD8+ T cell responses and high HIV loads. Furthermore, subjects with a severely depleted and phenotypically altered CD4+ T cell compartment had circulating Gag-specific CD8+ T cells with impaired IFN-γ production. When viral load was not suppressed by antiviral treatment, subjects that fell below the putative age and CD4+ T cell count thresholds had significantly reduced CD8+ T cell responses and significantly higher viral loads. Thus, the data suggest that fully effective HIV-specific CD8+ T cell responses take years to develop despite an abundance of Ag in early life, and responses are further severely impaired, independent of age, in children who have a depleted or skewed CD4+ T cell compartment. The results are discussed in relation to differences between the neonatal and adult immune systems in the ability to respond to HIV infection.
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Multiple studies have confirmed that programmed cell death 1/programmed cell death ligand-1 (PD-1/PD-L1) and immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 play pivotal roles in the treatment of numerous tumors. Patients suffering from cancer are provided hope in the form of immunotherapy. In this review, we discuss the finding that high PD-L1 expression is associated with poor clinical outcomes in prostate cancer patients. Some molecules exert their antitumor effects by downregulating PD-L1 expression in prostate cancer. Additionally, we discuss and summarize the important roles played by anti-PD-1/PD-L1 immunotherapy and its combination with other drugs, including chemotherapy and vaccines, in the treatment of prostate cancer.
Cancer Immunotherapy
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Urothelial bladder cancer displays a high number of somatic mutations that render these tumors more responsive to immunotherapy. Several immunotherapeutic agents were examined in patients with advanced stage urothelial bladder cancer and recently atezolizumab - an (PDL-1) immune checkpoint inhibitor antibody - was approved for the treatment of patients with metastatic disease progressing after platinum combination therapy. Despite the great success, there are still some unanswered questions and ongoing trials that are in progress to define the role of combination therapy and sequencing strategies. The objective of our manuscript is to summarize the most recent data on immunotherapy in advanced urothelial cancer. Current challenges and future perspectives of immunotherapy as a monotherapy or in combination strategies will also be analyzed.
Atezolizumab
Urothelial cancer
Cancer Immunotherapy
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