Spatial transcriptomics reveals prognostically LYZfibroblasts and colocalization with FN1macrophages in diffuse large B-cell lymphoma.

in Cancer immunology, immunotherapy : CII by Liyuan Dai, Ning Lou, Liling Huang, Lin Li, Le Tang, Yuankai Shi, Xiaohong Han

TLDR

  • The study identifies a prognostically relevant subtype of fibroblasts and macrophages in DLBCL patients, potentially serving as biomarkers for improving patient outcomes.
  • The hub genes associated with these subtypes may be targeted for developing novel therapeutic strategies in DLBCL.

Abstract

Diffuse large B-cell lymphoma (DLBCL) is a clinically heterogeneous malignancy with diverse patient outcomes, largely influenced by the tumor microenvironment (TME). Understanding the roles of fibroblasts and macrophages within the TME is essential for developing personalized therapeutic strategies in DLBCL. This study is a multi-omics approach, integrating spatial transcriptomics (n = 11), bulk transcriptomics (n = 2,499), immunohistochemistry (IHC, n = 37), multiplex immunofluorescence (mIF, n = 56), and plasma samples (n = 240) to identify and characterize fibroblast and tumor-associated macrophage subtypes in the TME. Hub genes for LYZfibroblasts and FN1macrophages were selected through univariate Cox regression and random forest analyses. Their prognostic significance was validated using IHC, mIF, and autoantibody assays in DLBCL patients treated with R-CHOP and in non-small cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs). Fibroblasts and macrophages were classified into two distinct subtypes. Patients with higher LYZfibroblasts infiltration demonstrated superior prognosis, which was associated with increased infiltration of FN1macrophages. Key hub genes identified for LYZfibroblasts included LYZ, ANPEP, CSF3R, C15orf48, LILRB4, CLEC7A, and COL7A1, while hub FN1macrophages genes included COL1A1, FN1, APOE, DCN, MMP2, SPP1, COL3A1, and COL1A2. Independent prognostic markers in DLBCL treated with R-CHOP and NSCLC treated with ICIs were identified, including LYZ and LILRB4 at both protein and mRNA levels, and COL1A2 autoantibodies (p < 0.05). In DLBCL patients treated with R-CHOP, FN1 mRNA and autoantibody levels were also prognostic markers (p < 0.05). In NSCLC treated with ICIs, COL3A1 autoantibody was prognostic marker (p < 0.05). This study identified a prognostically relevant LYZfibroblasts and FN1macrophages in DLBCL. The hub genes associated with these subtypes represent potential biomarkers, providing insights into improving patient outcomes in DLBCL.

Overview

  • The study aims to identify and characterize fibroblast and tumor-associated macrophage subtypes in the tumor microenvironment (TME) of diffuse large B-cell lymphoma (DLBCL) patients.
  • The study integrates multi-omics approaches, including spatial transcriptomics, bulk transcriptomics, immunohistochemistry, multiplex immunofluorescence, and plasma samples.
  • The primary objective of the study is to identify potential biomarkers for improving patient outcomes in DLBCL.

Comparative Analysis & Findings

  • The study identified two distinct subtypes of fibroblasts and macrophages in the TME of DLBCL patients.
  • Patients with higher infiltration of LYZfibroblasts demonstrated superior prognosis, which was associated with increased infiltration of FN1macrophages.
  • The hub genes associated with LYZfibroblasts and FN1macrophages were found to be prognostic markers in DLBCL patients treated with R-CHOP and NSCLC patients receiving immune checkpoint inhibitors.

Implications and Future Directions

  • The study's findings suggest that targeting LYZfibroblasts and FN1macrophages may improve patient outcomes in DLBCL.
  • Future studies should explore the molecular mechanisms underlying the association between LYZfibroblasts and FN1macrophages and patient prognosis.
  • The hub genes identified in this study may serve as potential biomarkers for patient stratification and personalized treatment in DLBCL.
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