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Deficient (d) DNA mismatch repair (MMR) is a biomarker predictive of better response to PD-1 blockade immunotherapy in solid tumors. dMMR can be caused by mutations in MMR genes or by protein inactivation, which can be detected by sequencing and immunohistochemistry, respectively. To investigate the role of dMMR in diffuse large B-cell lymphoma (DLBCL), MMR gene mutations and expression of MSH6, MSH2, MLH1, and PMS2 proteins were evaluated by targeted next-generation sequencing and immunohistochemistry in a large cohort of DLBCL patients treated with standard chemoimmunotherapy, and correlated with the tumor immune microenvironment characteristics quantified by fluorescent multiplex immunohistochemistry and gene-expression profiling. The results showed that genetic dMMR was infrequent in DLBCL and was significantly associated with increased cancer gene mutations and favorable immune microenvironment, but not prognostic impact. Phenotypic dMMR was also infrequent, and MMR proteins were commonly expressed in DLBCL. However, intratumor heterogeneity existed, and increased DLBCL cells with phenotypic dMMR correlated with significantly increased T cells and PD-1+ T cells, higher average nearest neighbor distance between T cells and PAX5+ cells, upregulated immune gene signatures, LE4 and LE7 ecotypes and their underlying Ecotyper-defined cell states, suggesting the possibility that increased T cells targeted only tumor cell subsets with dMMR. Only in patients with MYC¯ DLBCL, high MSH6/PMS2 expression showed significant adverse prognostic effects. This study shows the immunologic and prognostic effects of genetic/phenotypic dMMR in DLBCL, and raises a question on whether DLBCL-infiltrating PD-1+ T cells target only tumor subclones, relevant for the efficacy of PD-1 blockade immunotherapy in DLBCL. [ABSTRACT FROM AUTHOR]

Genetic and epigenetic aberrations display an essential role in the initiation and progression of diffuse large B-cell lymphoma (DLBCL). 5-methylcytosine (m 5 C), a common RNA modification, regulates various cellular processes and contributes to tumorigenesis and cancer progression. However, m 5 C alterations in DLBCL remain unclear. Our research constructed an m 5 C prognostic model utilizing GEO data sets, which can efficiently predict the prognosis of patients with DLBCL, and verified the m 5 C prognostic model genes by immunohistochemistry analysis. This model was constructed using unsupervised consensus clustering analyses, Least Absolute Shrinkage and Selection Operator (LASSO), and multivariate Cox regression analyses. Based on the expression of m 5 C genes in the model, patients with DLBCL could be effectively divided into groups with significant survival time differences. The m 5 C risk-score signature demonstrated a highly significant independent prognostic value. Results from tumor microenvironment analyses revealed that m 5 C genes altered the infiltration of eosinophils, Tregs, and M2 macrophages. Additionally, they regulated T cell activation by modulating the expression of CTLA4, PDL1, B2M, CD8A, ICOS, and other relevant immune checkpoint expressions. In conclusion, our study presents a robust m 5 C prognostic model that effectively predicts prognosis in DLBCL. This model may offer a new approach for prognostic stratification and potential therapeutic interventions for patients with DLBCL., Competing Interests: None., (AJCR Copyright © 2024.)

Lipid metabolism is associated with lymphomagenesis and functions as a new therapeutic target in patients with lymphoma. Several serum lipids and lipoproteins have prognostic value in solid tumors; however, their value in diffuse large B-cell lymphoma (DLBCL) has been poorly described. We retrospectively analyzed and compared pre-treatment serum lipid and lipoprotein levels, including triacylglycerol (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-I (ApoA-I), and apolipoprotein B (ApoB) between 105 DLBCL and 105 controls (no DLBCL). The prognostic significance of serum lipid and lipoprotein levels was determined using univariate and multivariate Cox proportional hazards models. The primary outcomes, overall survival (OS) and progression-free survival (PFS), were assessed by the Kaplan-Meier method. We combined the International Prognostic Index (IPI) with ApoA-I to build a nomogram model (IPI-A) to predict the OS and PFS of DLBCL. Serum TG, LDL-C, HDL-C, ApoA-I, and ApoB levels were significantly lower in the DLBCL patients than in controls and significantly increased after chemotherapy. Multivariate analyses showed that the ApoA-I level was an independent predictor of OS and PFS. In addition, our findings indicated that the prognostic index IPI-A significantly improves risk prediction over the traditional IPI score system. ApoA-I is an independent prognostic factor associated with poor OS and PFS in DLBCL patients. Our findings suggested that IPI-A is a prognostic index accurately used for risk assessment in patients with DLBCL., Competing Interests: None., (AJCR Copyright © 2023.)