Hodgkin lymphoma is characterized by an extensively dominant tumor microenvironment (TME) composed of different types of noncancerous immune cells with rare malignant cells. Characterization of the cellular components and their spatial relationship is crucial to understanding cross-talk and therapeutic targeting in the TME. We performed single-cell RNA sequencing of more than 127,000 cells from 22 Hodgkin lymphoma tissue specimens and 5 reactive lymph nodes, profi ling for the fi rst time the phenotype of the Hodgkin lymphoma-specifi c immune microenvironment at single-cell resolution. Single-cell expression profi ling identifi ed a novel Hodgkin lymphoma-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-defi cient tumor cells. Our fi ndings provide novel insights into TME biology and suggest new approaches to immune-checkpoint targeting in Hodgkin lymphoma. SIGNIFICANCE:We provide detailed functional and spatial characteristics of immune cells in classic Hodgkin lymphoma at single-cell resolution. Specifi cally, we identifi ed a regulatory T-cell-like immunosuppressive subset of LAG3 + T cells contributing to the immune-escape phenotype. Our insights aid in the development of novel biomarkers and combination treatment strategies targeting immune checkpoints.

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Sera from 76 patients with a clinical diagnosis of idiopathic rapidly progressive sensorineural hearing loss (SNHL) (n = 15), sudden deafness (n = 31) and with other etiologies of their hearing loss (n = 30) were analysed by western blot assay. Seventy-three percent of the cases with rapidly progressive SNHL had cross-reacting antibodies (27, 45, 50, 68 kD). The overall response to immunoprogressive therapy was effective in only 50% of cases. Sixty-five percent of the patients with sudden deafness also had cross-reacting antibodies (27, 45, 50, 80 kD). In these cases steroid therapy was more effective in re-establishing the hearing than no treatment, regardless of the western blot outcome. Spontaneous recovery occurred in approx. 50% of cases, but only in those with a positive assay. The antigenic epitopes detected with immunoblotting were not cochlea specific; they were also found in protein extracts of other organs (cranial nerves, kidney, brain).