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Diffuse large B‐cell lymphoma (DLBCL) is a genetically heterogeneous disease with complex tumor microenvironment (TME) alterations. However, immune cell signatures of TME and their prognostic value remain unclear in DLBCL. We aimed to identify high‐risk DLBCL with specific immune cell signatures in TME. Clinical and gene expression data of DLBCL patients were obtained from previously reported retrospective datasets in Gene Expression Omnibus (GSE108466 and GSE5378616) and a multi‐center prospective clinical trial NHL001 (NCT01852435). Patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen (n = 159) from GSE10846 were referred as training cohort for CHOP regimen, while patients treated with rituximab‐CHOP (R‐CHOP) regimen (n = 192) from GSE10846 as training cohort for R‐CHOP regimen. Patients from NHL001 (n = 68) and GSE53786 (n = 57) were referred as validation cohorts for R‐CHOP regimen. CIBERSORT was applied to estimate the relative proportions of 22 subtype of immune cells. We established a prognostic model for model for R‐CHOP regimen included Age, performance status, lactate dehydrogenase, T cells follicular helper and macrophages M0, defining a low‐risk group with 2‐years OS of 92.9% and a high‐risk group with 2‐years OS of 52.5% (HR 6.57 [3.27–13.18], p < 0.0001). Immune cell signatures could be used as prognostic markers and provided further insights for individualized immunotherapeutic strategies in DLBCL. [ABSTRACT FROM AUTHOR]

Background: Diffuse large B‐cell lymphoma (DLBCL) is an aggressive subtype of lymphoma, and multiple extranodal involvement (ENI) indicates adverse clinical outcomes. The aim of this study was to investigate the influence of oncogenic mutations and tumor microenvironment alterations on ENI in DLBCL. Methods: The clinical features of 1960 patients with newly diagnosed DLBCL were analyzed, and DNA and RNA sequencing was performed on 670 and 349 patients, respectively. Oncogenic mutations and tumor microenvironment alterations were compared according to ENI and evaluated in zebrafish patient‐derived tumor xenograft models. Results: Multiple ENI was significantly associated with poor performance status, advanced stage, elevated serum lactate dehydrogenase, low response rate, and inferior prognosis. Lymphoma invasion of the bones, spleen, bone marrow, liver, and central nervous system were independent unfavorable prognostic factors. MYD88 was frequently mutated in patients with multiple ENI, co‐occurred with mutations in CD79B, PIM1, TBL1XR1, BTG1, MPEG1, and PRDM1, and correlated with invasion of the bones, kidney/adrenal glands, breasts, testes, skin, and uterus/ovaries. For tumor microenvironment alterations, patients with multiple ENI showed higher regulatory T‐cell (Treg)‐recruiting activity, but lower extracellular matrix‐encoding gene expression, than those without ENI and with single ENI. Elevated Treg‐recruiting activity was related to mutations in B2M, SGK1, FOXO1, HIST1H1E, and ARID1A, and correlated with invasion of the bone marrow and thyroid. Additionally, mutations in MYD88, PIM1, TBL1XR1, SGK1, FOXO1, HIST1H1E, and ARID1A were associated with decreased major histocompatibility complex class I expression. Zebrafish models further revealed relationships between MYD88 mutations and invasion of the kidneys and gonads, as well as B2M mutations and invasion of the bone marrow. Increased CXCR4 expression is linked to bone marrow invasion in an organotropic way. Conclusions: Our findings thus contribute to an improved understanding of the biological behavior of multiple ENI and provide a clinical rationale for targeting ENI in DLBCL. [ABSTRACT FROM AUTHOR]