Single cell transcriptome analysis reveals disease-defining T cell subsets in the tumor microenvironment of classic Hodgkin lymphoma.

Hodgkin lymphoma (HL) is characterized by an extensively dominant tumor microenvironment (TME) composed of different types of non-cancerous immune cells with rare malignant cells. Characterization of the cellular components and their spatial relationship is crucial to understanding crosstalk and therapeutic targeting in the TME. We performed single-cell RNA sequencing of more than 127,000 cells from 22 HL tissue specimens and 5 reactive lymph nodes, profiling for the first time the phenotype of the HL-specific immune microenvironment at single-cell resolution. Single-cell expression profiling identified a novel HL-associated subset of T cells with prominent expression of the inhibitory receptor LAG3, and functional analyses established this LAG3+ T cell population as a mediator of immunosuppression. Multiplexed spatial assessment of immune cells in the microenvironment also revealed increased LAG3+ T cells in the direct vicinity of MHC class-II deficient tumor cells. Our findings provide novel insights into TME biology and suggest new approaches to immune checkpoint targeting in HL.

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