Prognostic Impact of the Immunoscore Based on Whole-Slide Image Analysis of CD3+ Tumor-Infiltrating Lymphocytes in Diffuse Large B-Cell Lymphoma

Han, Bogyeong; Yim, Jeemin; Lim, Sojung; Na, S.Y.; Lee, Cheol; Kim, Tae Min; Paik, Jin-Ho; Kim, Sehui; Jeon, Yoon Kyung

doi:10.1016/j.modpat.2023.100224

Cited by 6 publications

(4 citation statements)

References 29 publications

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“…Flow cytometry and IHC are complementary clinical practices that are routinely used for the diagnosis of hematologic neoplasms. A recent study demonstrated that high immunoscores based on CD3 and CD20 IHC staining, routinely performed in the clinic, were significantly associated with favorable clinical outcome ( 36 ); however, routine IHC could not distinguish between normal and abnormal B cells. Compared to IHC, flow cytometry uses larger fresh tissues and is more sensitive to detect selected marker expression ( 37 ).…”

Section: Discussionmentioning

confidence: 99%

“…The prognostic cutoffs for T cells by flow cytometry in the literature were slightly higher than ours, including 20% and 14% cutoffs for low T cell proportion in two previous flow cytometry studies ( 31 , 33 ) and a 23% median cutoff for percentage of CD4 T cells in another study ( 32 ). A recent study using digitally quantified CD3+ and CD20+ scores by chromogenic IHC on whole slides of DLBCL tissues adopted much higher cutoffs for CD3+ cells with significant prognostic effects in the studied 104 DLBCL cases: the cutoff for high CD3+ percentage in all cells was at the top 21 percentile, and the cutoff for high CD3+ to CD20+ ratio was at the top 47 percentile ( 36 ). In a previous study by Autio et al.…”

Section: Discussionmentioning

confidence: 99%

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Flow cytometry quantification of tumor-infiltrating lymphocytes to predict the survival of patients with diffuse large B-cell lymphoma

Yu,

Xu-Monette,

Lagoo

et al. 2024

Front. Immunol.

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IntroductionOur previous studies have demonstrated that tumor-infiltrating lymphocytes (TILs), including normal B cells, T cells, and natural killer (NK) cells, in diffuse large B-cell lymphoma (DLBCL) have a significantly favorable impact on the clinical outcomes of patients treated with standard chemoimmunotherapy. In this study, to gain a full overview of the tumor immune microenvironment (TIME), we assembled a flow cytometry cohort of 102 patients diagnosed with DLBCL at the Duke University Medical Center.MethodsWe collected diagnostic flow cytometry data, including the proportion of T cells, abnormal B cells, normal B cells, plasma cells, NK cells, monocytes, and granulocytes in fresh biopsy tissues at clinical presentation, and analyzed the correlations with patient survival and between different cell populations.ResultsWe found that low T cell percentages in all viable cells and low ratios of T cells to abnormal B cells correlated with significantly poorer survival, whereas higher percentages of normal B cells among total B cells (or high ratios of normal B cells to abnormal B cells) and high percentages of NK cells among all viable cells correlated with significantly better survival in patients with DLBCL. After excluding a small number of patients with low T cell percentages, the normal B cell percentage among all B cells, but not T cell percentage among all cells, continued to show a remarkable prognostic effect. Data showed significant positive correlations between T cells and normal B cells, and between granulocytes and monocytes. Furthermore, we constructed a prognostic model based on clinical and flow cytometry factors, which divided the DLBCL cohort into two equal groups with remarkable differences in patient survival and treatment response.SummaryTILs, including normal B cells, T cells, and NK cells, are associated with favorable clinical outcomes in DLBCL, and flow cytometry capable of quantifying the TIME may have additional clinical utility for prognostication.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Flow cytometry quantification of tumor-infiltrating lymphocytes to predict the survival of patients with diffuse large B-cell lymphoma

Yu,

Xu-Monette,

Lagoo

et al. 2024

Front. Immunol.

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“…The slides were mounted with neutral gum after ethanol dehydration and xylene clearing. After the images were saved, pathological changes were observed by using an Aperio ScanScope CS2 scanner (Leica, Biosystems, Vista, CA, USA) via the analysis software Aperio Imagescope (version 12.4.6), which is a Digital Pathology Analysis System (Leica, Biosystems, Vista, CA, USA, version 102.0.7.5) 5 – 7 , 35 – 37 . The entire spleen region was selected for analysis, and protein expression was assessed by using the nuclear V9 and membrane V9 algorithms of this software.…”

Section: Methodsmentioning

confidence: 99%

Pathological changes in the spleen of mice subjected to different time courses of restraint stress

Lei,

Li,

et al. 2024

Sci Rep

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The objective of this study was to investigate spleen pathology and immune cell subset alterations in mice exposed to acute and chronic restraint stress over various timeframes. A deeper understanding of stress-induced spleen injuries can provide new insights into the mechanisms underlying stress-induced disorders. C57BL/6N mice were restrained for different durations (1, 3, 7, 14 and 21 days) for 6–8 h daily. The control mice were observed at the same time points. Post restraint, behavioural experiments were conducted to assess spleen weight, gross morphology and microscopic histological changes. Immunohistochemical staining was used to detect changes in glucocorticoid receptor (GR) expression, immune cell subsets and cell proliferation in response to stress. Our analysis revealed significant behavioural abnormalities in the stressed mice. In particular, there was an increase in the nuclear expression of GR beginning on Day 3, and it peaked on Day 14. The spleens of stressed mice displayed a reduction in size, disordered internal tissue structure and reduced cell proliferation. NK cells and M2-type macrophages exhibited immune cell subset alterations under stress, whereas T or B cells remained unaltered. Restraint stress can lead to pathomorphological alterations in spleen morphology, cell proliferation and immune cell counts in mice. These findings suggest that stress-induced pathological changes can disrupt immune regulation during stress.

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“…Understanding the tumor immune microenvironment is essential in immunotherapy. T-cell-in amed tumors exhibit a favorable prognosis, while T-cell-non-in amed and/or immunosuppressive cell-rich tumors have a worse prognosis and show resistance to immunotherapies in lymphomas [12][13][14]. The immune landscape of tumors is primarily in uenced by the local chemokine milieu [15].…”

Section: Introductionmentioning

confidence: 99%

Increased CCL2/CCR2 axis promotes tumor progression by increasing M2 macrophages in MYC/BCL2 double-expressor diffuse large B-cell lymphoma

Jeon,

Kim,

Jeong

et al. 2024

Preprint

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The pathogenesis of MYC and BCL2 double expressor diffuse large B-cell lymphoma (DE-DLBCL) remains unclear. To investigate how MYC and BCL2 contribute to tumor aggressiveness, we analyzed tumors from 14 patients each with DE- and non-DE-DLBCL patients by whole transcriptome sequencing. Validation was performed using publicly available datasets, tumor tissues from 126 patients, DLBCL cell lines, and a syngeneic mouse lymphoma model. Our transcriptome analysis revealed significantly elevated mRNA levels of C-C motif chemokine ligand 2 (CCL2) and C-C chemokine receptor type 2 (CCR2) in DE-DLBCLs compared to non-DE-DLBCLs (Padj < 0.05). Transcriptomic analysis with public datasets and immunohistochemistry corroborated these findings, indicating heightened M2 macrophage presence but diminished T-cell infiltration in DE-DLBCLs compared to non-DE-DLBCLs (all, P < 0.05). MYChigh/BCL2high DLBCL cells showed higher CCL2 secretion than MYClow/BCL2low cells. MYC and BCL2 increased CCL2 secretion by upregulation of nuclear factor-κB p65 in DLBCL cells, and the CCL2 promoted M2 polarization of macrophages. In a mouse lymphoma model, CCL2 contributed to the immunosuppressive microenvironment and tumor growth. We demonstrated that the increased CCL2/CCR2 axis confers aggressiveness to DE-DLBCL by increasing M2 polarization and can be a potential therapeutic target.

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Prognostic Impact of the Immunoscore Based on Whole-Slide Image Analysis of CD3+ Tumor-Infiltrating Lymphocytes in Diffuse Large B-Cell Lymphoma

Cited by 6 publications

References 29 publications

Flow cytometry quantification of tumor-infiltrating lymphocytes to predict the survival of patients with diffuse large B-cell lymphoma

Flow cytometry quantification of tumor-infiltrating lymphocytes to predict the survival of patients with diffuse large B-cell lymphoma

Pathological changes in the spleen of mice subjected to different time courses of restraint stress

Increased CCL2/CCR2 axis promotes tumor progression by increasing M2 macrophages in MYC/BCL2 double-expressor diffuse large B-cell lymphoma

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