Spatially-resolved Transcriptomics Reveal Macrophage Heterogeneity and Prognostic Significance in Diffuse Large B-cell Lymphoma (Nature Communications, Mar 2024)

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Min Liu 1 2 3, Giorgio Bertolazzi 4 5, Shruti Sridhar 1, Rui Xue Lee 1, Patrick Jaynes 1, Kevin Mulder 6 7 8, Nicholas Syn 9 10, Michal Marek Hoppe 1, Shuangyi Fan 9, Yanfen Peng 1, Jocelyn Thng 1, Reiya Chua 11, Jayalakshmi 11, Yogeshini Batumalai 11, Sanjay De Mel 11 12, Limei Poon 11 12, Esther Hian Li Chan 11 12, Joanne Lee 11 12, Susan Swee-Shan Hue 9 12, Sheng-Tsung Chang 13, Shih-Sung Chuang 13, K George Chandy 14, Xiaofei Ye 15, Qiang Pan-Hammarström 16, Florent Ginhoux 6 7 8, Yen Lin Chee 11 12, Siok-Bian Ng 1 9 12, Claudio Tripodo 17 18, Anand D Jeyasekharan 19 20 21 22

Affiliations

  • 1Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
  • 2Department of Radiation Oncology, Chongqing University Cancer Hospital, Chongqing, PR China.
  • 3Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, PR China.
  • 4Department of Economics, Business and Statistics, University of Palermo, Palermo, Italy.
  • 5Tumor Immunology Unit, Department of Sciences for Health Promotion and Mother-Child Care “G. D’Alessandro”, University of Palermo, Palermo, Italy.
  • 6Singapore Immunology Network, Agency for Science, Technology and Research, Singapore, Singapore.
  • 7Institut National de la Santé Et de la Recherche Medicale (INSERM) U1015, Equipe Labellisée-Ligue Nationale contre le Cancer, Villejuif, France.
  • 8Université Paris-Saclay, Gustave Roussy, Villejuif, France.
  • 9Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 10Department of Biomedical Informatics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 11Department of Haematology-Oncology, National University Health System, Singapore, Singapore.
  • 12NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 13Department of Pathology, Chi-Mei Medical Center, Tainan City, Taiwan, ROC.
  • 14Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore.
  • 15Kindstar Global Precision Medicine Institute, Wuhan, PR China.
  • 16Division of Immunology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
  • 17Tumor Immunology Unit, Department of Sciences for Health Promotion and Mother-Child Care “G. D’Alessandro”, University of Palermo, Palermo, Italy. claudio.tripodo@unipa.it.
  • 18Histopathology Unit, Institute of Molecular Oncology Foundation (IFOM) ETS – The AIRC Institute of Molecular Oncology, Milan, Italy. claudio.tripodo@unipa.it.
  • 19Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. csiadj@nus.edu.sg.
  • 20Department of Haematology-Oncology, National University Health System, Singapore, Singapore. csiadj@nus.edu.sg.
  • 21NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. csiadj@nus.edu.sg.
  • 22Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. csiadj@nus.edu.sg.

Abstract

Macrophages are abundant immune cells in the microenvironment of diffuse large B-cell lymphoma (DLBCL). Macrophage estimation by immunohistochemistry shows varying prognostic significance across studies in DLBCL, and does not provide a comprehensive analysis of macrophage subtypes. Here, using digital spatial profiling with whole transcriptome analysis of CD68+ cells, we characterize macrophages in distinct spatial niches of reactive lymphoid tissues (RLTs) and DLBCL. We reveal transcriptomic differences between macrophages within RLTs (light zone /dark zone, germinal center/ interfollicular), and between disease states (RLTs/ DLBCL), which we then use to generate six spatially-derived macrophage signatures (MacroSigs). We proceed to interrogate these MacroSigs in macrophage and DLBCL single-cell RNA-sequencing datasets, and in gene-expression data from multiple DLBCL cohorts. We show that specific MacroSigs are associated with cell-of-origin subtypes and overall survival in DLBCL. This study provides a spatially-resolved whole-transcriptome atlas of macrophages in reactive and malignant lymphoid tissues, showing biological and clinical significance.

PMID: 38459052        DOI: 10.1038/s41467-024-46220-z

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