Immune phenotypes and checkpoint molecule expression of clonally expanded lymph node-infiltrating T cells in classical Hodgkin lymphoma

• DOI: 10.1007/s00262-022-03264-8
• Publication Date: 2022-08-10T12:02:40Z
• Authors: Alexej Ballhausen; Amin Ben Hamza; Carlotta Welters; Kerstin Dietze; Lars Bullinger; Hans-Peter Rahn; Sylvia Hartmann; Martin-Leo Hansmann; Leo Hansmann
• Keywords: Research Report; Cancer Research; 0303 health sciences; Lymphoma immunology; 610; T cell receptor sequencing; Single cell technologies; CD8-Positive T-Lymphocytes; Hodgkin Disease; Lymph node-infiltrating T cells; 3. Good health; 03 medical and health sciences; Phenotype; Lymphocytes, Tumor-Infiltrating; Tumor Microenvironment; Integrative Biomedicine [Topic 3]; Humans; Lymph Nodes; Technology Platforms; Immune Checkpoint Inhibitors; Hodgkin lymphoma; Immune checkpoint blockade; 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit

AbstractLymph node-infiltrating T cells have been of particular interest in classical Hodgkin lymphoma (cHL). High rates of complete therapeutic responses to antibody-mediated immune checkpoint blockade, even in relapsed/refractory patients, suggest the existence of a T cell-dominated, antigen-experienced, functionally inhibited and lymphoma-directed immune microenvironment. We asked whether clonally expanded T cells (1) were detectable in cHL lymph nodes, (2) showed characteristic immune phenotypes, and (3) were inhibited by immune checkpoint molecule expression. We applied high-dimensional FACS index sorting and single cell T cell receptor αβ sequencing to lymph node-infiltrating T cells from 10 treatment-naïve patients. T cells were predominantly CD4+ and showed memory differentiation. Expression of classical immune checkpoint molecules (CTLA-4, PD-1, TIM-3) was generally low (< 12.0% of T cells) and not different between CD4+ and CD8+ T cells. Degrees of clonal T cell expansion varied between patients (range: 1–18 expanded clones per patient) and was almost exclusively restricted to CD8+ T cells. Clonally expanded T cells showed non-naïve phenotypes and low checkpoint molecule expression similar to non-expanded T cells. Our data suggest that the therapeutic effects of immune checkpoint blockade require mechanisms in addition to dis-inhibition of pre-existing lymphoma-directed T cell responses. Future studies on immune checkpoint blockade-associated effects will identify molecular T cell targets, address dynamic aspects of cell compositions over time, and extend their focus beyond lymph node-infiltrating T cells.