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Microbial dysbiosis is associated with aggressive histology and adverse clinical outcome in B-cell non-Hodgkin lymphoma.

ABSTRACT: B-cell non-Hodgkin lymphoma cell survival depends on poorly understood immune evasion mechanisms. In melanoma, the composition of the gut microbiota (GMB) is associated with immune system regulation and response to immunotherapy. We investigated the association of GMB composition and diversity with lymphoma biology and treatment outcome. Patients with diffuse large B-cell lymphoma (DLBCL), marginal zone (MZL), and follicular lymphoma (FL) were recruited at Mayo Clinic, Minnesota, and Perlmutter Cancer Center, NYU Langone Health. The pretreatment GMB was analyzed using 16S ribosomal RNA gene sequencing. We examined GMB compositions in 3 contexts: lymphoma patients (51) compared with healthy controls (58), aggressive (DLBCL) (8) compared with indolent (FL, MZL) (18), and the association of GMB with immunochemotherapy treatment outcomes (8 responders, 6 nonresponders). Respectively, we found that the pretreatment GMB in lymphoma patients had a distinct composition compared with healthy controls (P < .001); GMB compositions in DLBCL patients were significantly different than indolent patients (P = .01) with a trend toward reduced microbial diversity in DLBCL patients (P = .08); and pretreatment GMB diversity and composition were significant predictors of treatment responses (P = .01). The impact of these pilot results is limited by our small sample size, and should be considered a proof of principle. If validated, our results could lead toward improved treatment outcomes by improving medication stewardship and informing which GMB-targeted therapies should be tested to improve patient outcomes.

SUBMITTER: Diefenbach CS

PROVIDER: S-EPMC7948261 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Microbial dysbiosis is associated with aggressive histology and adverse clinical outcome in B-cell non-Hodgkin lymphoma.

Diefenbach Catherine S CS Peters Brandilyn A BA Li Huilin H Raphael Bruce B Moskovits Tibor T Hymes Kenneth K Schluter Jonas J Chen J J Bennani N Nora NN Witzig Thomas E TE Ahn Jiyoung J

Blood advances 20210301 5

B-cell non-Hodgkin lymphoma cell survival depends on poorly understood immune evasion mechanisms. In melanoma, the composition of the gut microbiota (GMB) is associated with immune system regulation and response to immunotherapy. We investigated the association of GMB composition and diversity with lymphoma biology and treatment outcome. Patients with diffuse large B-cell lymphoma (DLBCL), marginal zone (MZL), and follicular lymphoma (FL) were recruited at Mayo Clinic, Minnesota, and Perlmutter ...[more]

PMID: 33635332

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Project description:We have previously reported a novel constitutively overexpressed 21 kDa protein in Hodgkin Lymphoma (HL) and aggressive Non-Hodgkin Lymphomas (NHL). The objective of the current study was to 1) identify this protein using two independent methods, 2) study the expression of the protein and its encoding mRNA in reactive lymph nodes, normal lymphocytes and CD34+ bone marrow precursor cells, 3) analyse patterns of expression of the protein in tissue microarrays assembled from a large number of diagnostic clinical biopsies from patients with HL, and 4) determine the copy number variation and mutation status of the encoding gene in HL cell lines.Peptide sequencing by LC-MS/MS and protein identification by protein array screening identified a single protein, CYB5B. No mutations were detected in the CYB5B gene in HL cell lines. Quantitative PCR showed CYB5B gene expression was increased in HL and NHL cell lines. Array CGH using a submegabase resolution tiling array revealed gains in the CYB5B locus in HL cell lines KMH2 and L428. Membrane expression was seen in Reed-Sternberg cells in clinical biopsies from patients with HL but not in reactive lymph nodes. Bone marrow CD34+ precursor cells were CYB5B negative on the cell surface. RT-PCR assays of RNA extracted from T and B cell enriched fractions obtained from normal peripheral blood mononuclear cells, reactive lymph nodes, tonsils and normal bone marrow samples showed no evidence of increased mRNA levels of CYB5B in comparison to housekeeping gene GAPDH.The 21 kDa protein overexpressed in HL and aggressive NHL is identical to CYB5B. CYB5B gene expression is increased in a subset of HL and NHL cell lines tested. This is associated with CYB5B gene amplification in HL cell lines KMH2 and L428. CYB5B may be a potential target for antibody-based therapy of HL and aggressive NHL as although cytoplasmic expression is present in reactive lymphocytes, it is not expressed on the cell surface of non-neoplastic lymphocytes or bone marrow precursor cells.

Project description:PurposeTo evaluate the prognostic utility of apparent diffusion coefficient (ADC) changes at whole-body diffusion-weighted (WB-DW) MRI after one treatment cycle for aggressive non-Hodgkin lymphoma (NHL) compared with response assessment at interim and end-of-treatment fluorine 18 (18F) fluorodeoxyglucose (FDG) PET/CT.Materials and methodsThis was a secondary analysis of a prospective study (ClinicalTrials.gov identifier: NCT01231269) in which participants with aggressive NHL were recruited between March 2011 and April 2015 and underwent WB-DW MRI before and after one cycle of immunochemotherapy. Volunteers were recruited for test-retest WB-DW MRI (ClinicalTrials.gov identifier: NCT01231282) to assess ADC measurement repeatability. Response assessment was based on ADC change after one treatment cycle at WB-DW MRI and Deauville criteria at 18F-FDG PET/CT. To evaluate prognostic factors of disease-free survival (DFS), Kaplan-Meier survival analysis and univariable and multivariable Cox regression were performed; intraclass correlation coefficient (ICC) and mean difference with limits of agreement were calculated to determine inter- and intraobserver repeatability of ADC measurements.ResultsForty-five patients (mean age, 58 years ± 17 [standard deviation]; 31 men) and nine volunteers (mean age, 22 years ± 3; seven men) were enrolled. Median DFS was 48 months (range, 2-48 months). Outcome prediction accuracy was 86.7% (39 of 45), 71.4% (30 of 42), and 73.8% (31 of 42) for WB-DW MRI and interim and end-of-treatment 18F-FDG PET/CT, respectively. WB-DW MRI (hazard ratio [HR], 17.8; P < .001) and interim (HR, 5; P = .008) and end-of-treatment (HR, 4.3; P = .017) 18F-FDG PET/CT were prognostic of DFS. After multivariable analysis, WB-DW MRI remained an independent predictor of outcome (HR, 26.8; P = .002). Intra- and interobserver agreement for ADC measurements were excellent (ICC = 0.85-0.99).ConclusionQuantitative WB-DW MRI after only one cycle of immunochemotherapy predicts DFS in aggressive NHL and is noninferior to routinely performed interim and end-of-treatment 18F-FDG PET/CT.Keywords: MR-Diffusion Weighted Imaging, Lymphoma, Oncology, Tumor Response, Whole-Body ImagingSupplemental material is available for this article.© RSNA, 2021.

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Dataset Information

Microbial dysbiosis is associated with aggressive histology and adverse clinical outcome in B-cell non-Hodgkin lymphoma.

Publications

Microbial dysbiosis is associated with aggressive histology and adverse clinical outcome in B-cell non-Hodgkin lymphoma.

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