Spatially-resolved transcriptomics reveal macrophage heterogeneity and prognostic significance in diffuse large B-cell lymphoma

Min Liu, Giorgio Bertolazzi, Shruti Sridhar, Rui Xue Lee, Patrick Jaynes, Kevin Mulder, Nicholas Syn, Michal Marek Hoppe, Shuangyi Fan, Yanfen Peng, Jocelyn Thng, Reiya Chua, Jayalakshmi, Yogeshini Batumalai, Sanjay De Mel, Limei Poon, Esther Hian Li Chan, Joanne Lee, Susan Swee-Shan Hue, Sheng-Tsung Chang, Shih-Sung Chuang, K. George Chandy, Xiaofei Ye, Qiang Pan-Hammarström, Florent Ginhoux, Yen Lin Chee, Siok-Bian Ng, Claudio Tripodo () and Anand D. Jeyasekharan ()
Additional contact information
Min Liu: National University of Singapore
Giorgio Bertolazzi: University of Palermo
Shruti Sridhar: National University of Singapore
Rui Xue Lee: National University of Singapore
Patrick Jaynes: National University of Singapore
Kevin Mulder: Technology and Research
Nicholas Syn: National University of Singapore
Michal Marek Hoppe: National University of Singapore
Shuangyi Fan: National University of Singapore
Yanfen Peng: National University of Singapore
Jocelyn Thng: National University of Singapore
Reiya Chua: National University Health System
Jayalakshmi: National University Health System
Yogeshini Batumalai: National University Health System
Sanjay De Mel: National University Health System
Limei Poon: National University Health System
Esther Hian Li Chan: National University Health System
Joanne Lee: National University Health System
Susan Swee-Shan Hue: National University of Singapore
Sheng-Tsung Chang: Chi-Mei Medical Center
Shih-Sung Chuang: Chi-Mei Medical Center
K. George Chandy: Nanyang Technological University Singapore
Xiaofei Ye: Kindstar Global Precision Medicine Institute
Qiang Pan-Hammarström: Karolinska Institutet
Florent Ginhoux: Technology and Research
Yen Lin Chee: National University Health System
Siok-Bian Ng: National University of Singapore
Claudio Tripodo: University of Palermo
Anand D. Jeyasekharan: National University of Singapore

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46220-z

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