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Flow Cytometry-Assessed PD1/PDL1 Status in Tumor-Infiltrating Lymphocytes: A Link With the Prognosis of Diffuse Large B-Cell Lymphoma.

ABSTRACT: The PD1/PDL1 status of tumor-infiltrating lymphocytes (TILs) in diffuse large B-cell lymphoma (DLBCL) reflects immune function. However, the previously reported methods for evaluating this status are complex and may not be widely used in clinical practice. In addition, these studies did not introduce healthy controls to designate the cut-off when evaluating the prognostic value of the status. In this study, we retrospectively evaluated the PD1/PDL1 status in TILs of 24 DLBCL tissue samples and normal immune cells in 61 demographically matched healthy controls (tissue samples from patients with reactive hyperplasia [RH]) by flow cytometry. We investigated the prognostic value of the PD1/PDL1 status in TILs by precisely determining the cut-off value and assessing the reliability of flow cytometry. The mean fluorescence intensity (MFI) of PD1 in TIL-T-cells (TIL-Ts; median, 110) and CD8+TIL-Ts (median, 64) was significantly higher than that of CD3+T-cells (median, 64) and CD8+ T-cells (median, 34) in RH. The cut-off values of PD1/PDL1 status for analyzing prognostic values were defined considering the PD1/PDL1 status of samples from both patients with DLBCL and healthy controls. High MFI of PD1 in TIL-Ts (MFI >108, P = 0.022), high proportion of PD1+CD4+TIL-Ts (>1.1% of CD4+TIL-Ts, P = 0.049), high proportion of PD1+CD8+TIL-Ts (>2% of CD8+TIL-Ts, P = 0.025), and high MFI of PDL1 in TIL-Ts (MFI >83, P = 0.023) were risk factors for inferior prognosis of DLBCL. Our results indicate that flow cytometry is a reliable and convenient method for evaluating the immune-checkpoint status of TILs, which probably holds major implications in clinical practice.

SUBMITTER: Chen Z

PROVIDER: S-EPMC8239303 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Natural microbial communities affect human life in countless ways, ranging from global biogeochemical cycles to the treatment of wastewater and health via the human microbiome. In order to probe, monitor, and eventually control these communities, fast detection and evaluation methods are required. In order to facilitate rapid community analysis and monitor a community's dynamic behavior with high resolution, we here apply community flow cytometry, which provides single-cell-based high-dimensional data characterizing communities with high acuity over time. To interpret time series data, we draw inspiration from macroecology, in which a rich set of concepts has been developed for describing population dynamics. We focus on the stability paradigm as a promising candidate to interpret such data in an intuitive and actionable way and present a rapid workflow to monitor stability properties of complex microbial ecosystems. Based on single-cell data, we compute the stability properties resistance, resilience, displacement speed, and elasticity. For resilience, we also introduce a method which can be implemented for continuous online community monitoring. The proposed workflow was tested in a long-term continuous reactor experiment employing both an artificial and a complex microbial community, which were exposed to identical short-term disturbances. The computed stability properties uncovered the superior stability of the complex community and demonstrated the global applicability of the protocol to any microbiome. The workflow is able to support high temporal sample densities below bacterial generation times. This may provide new opportunities to unravel unknown ecological paradigms of natural microbial communities, with applications to environmental, biotechnological, and health-related microbiomes. IMPORTANCE Microbial communities drive many processes which affect human well-being directly, as in the human microbiome, or indirectly, as in natural environments or in biotechnological applications. Due to their complexity, their dynamics over time is difficult to monitor, and current sequence-based approaches are limited with respect to the temporal resolution. However, in order to eventually control microbial community dynamics, monitoring schemes of high temporal resolution are required. Flow cytometry provides single-cell-based data in the required temporal resolution, and we here use such data to compute stability properties as easy to interpret univariate indicators of microbial community dynamics. Such monitoring tools will allow for a fast, continuous, and cost-effective screening of stability states of microbiomes. Applicable to various environments, including bioreactors, surface water, and the human body, it will contribute to the development of control schemes to manipulate microbial community structures and performances.

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Project description:BackgroundCD8+ tumor-infiltrating T lymphocytes (T-TILs) in the tumor microenvironment (TME) play an important role in tumor development, and miRNAs regulate tumor cell interactions with the microenvironment. T-TIL-based tumor immunotherapy provides a promising treatment strategy in diffuse large B-cell lymphoma (DLBCL). MiRNAs tend to be attractive targets for novel antitumor interventions.MethodsWeighted gene coexpression network analysis (WGCNA), CIBERSORT analysis and Cox regression analysis were used to identify CD8+ T-TIL-related miRNAs. RT-PCR, western blotting, immunohistochemistry (IHC), in situ hybridization (ISH), luciferase reporter assay, coimmunoprecipitation and ubiquitination analyses were used to detect miRNA, mRNA and protein expression and their combination. The viability and function of CD8+ T cells after stimulation were evaluated by enzyme-linked immunosorbent assay (ELISA), cytotoxicity assay, functional avidity assessment, flow cytometry and Cell Counting Kit-8 (CCK-8) assay. DLBCL cell lines, primary cells and a murine xenograft model established with A20 cell injection were used as in vitro and in vivo experimental models.ResultsMiR-340-5p was positively correlated with CD8+ T-TILs in DLBCL patients, and KMT5A was a direct target gene of miR-340-5p. CD8+ T-cell function was significantly enhanced by miR-340-5p mimics both in vitro and in vivo, which was reversed by KMT5A overexpression. We demonstrated that COP1/CD73 was involved in the downstream mechanism of the miR-340-5p/KMT5A axis involving ubiquitination. In vivo, we validated an improved CD8+ T-TIL infiltration rate and tumor suppression with miR-340-5p treatment. Furthermore, miR-340-5p directly regulated the biological activity of DLBCL cells without CD8+ T-cell participation.ConclusionsMiR-340-5p promoted CD8+ T-TIL infiltration and antitumor function by regulating KMT5A and COP1 and further activating CD73 ubiquitination. MiR-340-5p is potentially a novel target for DLBCL immunotherapy.

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Flow Cytometry-Assessed PD1/PDL1 Status in Tumor-Infiltrating Lymphocytes: A Link With the Prognosis of Diffuse Large B-Cell Lymphoma.

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