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by claude@2026-07, 2026-07-16
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This study used comparative spatial transcriptomic profiling of primary central nervous system lymphoma (PCNSL, n=17) versus systemic diffuse large B-cell lymphoma (n=76) to characterize tumor microenvironment features tied to PCNSL’s CNS tropism. It found increased macrophage infiltration in PCNSL, with macrophages showing immunosuppressive (SPP1+) and cholesterol metabolism signatures, then validated these patterns across three independent PCNSL scRNA-seq cohorts (n=8, 7, 13). The authors characterized these as lipid-laden macrophages resembling those described in glioblastoma, distinct from microglia, derived from infiltrating monocytes, with unique interactions with T-cells, and used hyperplex spatial proteomics to confirm GPNMB+ LLMs and relate the LLM–T cell distance to treatment response. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.
Abstract
Primary central nervous system lymphoma (PCNSL) is a subtype of diffuse large B-cell lymphoma (DLBCL) with confined CNS growth. We evaluated tumor microenvironment (TME) features associated with its unique tropism. Comparative spatial transcriptomic profiling of PCNSL samples (n=17) revealed increased macrophage infiltration compared to systemic DLBCL (n=76). These macrophages showed enrichment of immunosuppressive (SPP1⁺) and cholesterol metabolism signatures. These findings were validated across three independent PCNSL scRNA-seq cohorts (n=8,7,13), with further characterization as lipid-laden macrophages (LLMs)- like those noted in glioblastoma. These LLMs are transcriptionally distinct from microglia, derive from infiltrating monocytes, show activation of lipid metabolism, and have unique interactions with T-cells. Hyperplex spatial proteomics confirms GPNMB⁺ LLMs and identifies LLM-T cell distance as a correlate of treatment response. Together, our findings define a distinct feature of the TME in PCNSL and identify lipid-laden macrophages as a candidate population for immune modulation and therapeutic targeting. Statement of Significance This study identifies a lipid-laden macrophage population that is uniquely noted in PCNSL and not systemic DLBCL, similar to those in Glioblastoma. These are distinct from microglia, implicating metabolic macrophage reprogramming in PCNSL tropism and immune evasion. This integrated spatial multi-omics study details the unique macrophage landscape in PCNSL with potential therapeutic implications.
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Abstract
Primary central nervous system lymphoma (PCNSL) is a subtype of diffuse large B-cell lymphoma (DLBCL) with confined CNS growth. We evaluated tumor microenvironment (TME) features associated with its unique tropism. Comparative spatial transcriptomic profiling of PCNSL samples (n=17) revealed increased macrophage infiltration compared to systemic DLBCL (n=76). These macrophages showed enrichment of immunosuppressive (SPP1⁺) and cholesterol metabolism signatures. These findings were validated across three independent PCNSL scRNA-seq cohorts (n=8,7,13), with further characterization as lipid-laden macrophages (LLMs)- like those noted in glioblastoma. These LLMs are transcriptionally distinct from microglia, derive from infiltrating monocytes, show activation of lipid metabolism, and have unique interactions with T-cells. Hyperplex spatial proteomics confirms GPNMB⁺ LLMs and identifies LLM-T cell distance as a correlate of treatment response. Together, our findings define a distinct feature of the TME in PCNSL and identify lipid-laden macrophages as a candidate population for immune modulation and therapeutic targeting.
Statement of Significance This study identifies a lipid-laden macrophage population that is uniquely noted in PCNSL and not systemic DLBCL, similar to those in Glioblastoma. These are distinct from microglia, implicating metabolic macrophage reprogramming in PCNSL tropism and immune evasion. This integrated spatial multi-omics study details the unique macrophage landscape in PCNSL with potential therapeutic implications.
Competing Interest Statement
Anand D Jeyasekharan has declared consultancy fees and research funding that are unrelated to this work. He has received consultancy fees from DKSH/Beigene, Roche, Gilead, AstraZeneca, Antengene, Janssen, MSD, and IQVIA, as well as research funding from Janssen and AstraZeneca. The other co-authors have indicated that they have no relevant conflicts of interest to declare
Footnotes
↵* senior authors
Conflict of interest Disclosure:
Anand D. Jeyasekharan has received consultancy fees from DKSH/BeiGene, Roche, Gilead, Turbine Ltd, AstraZeneca, Antengene, Janssen, MSD, IQVIA, and KYAN Technologies, and research funding from Janssen and AstraZeneca; all of which are unrelated to this work.
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