Human Leucocyte Antigen (HLA) class I expression is an EBV-independent major determinator of microenvironment composition in classic Hodgkin Lymphoma and associated with a cytotoxic immune response

Abstract Hodgkin Reed Sternberg cells (HRSC) in classic Hodgkin Lymphoma (HL) frequently lack expression of human leucocyte antigen class I (HLA-I), hampering activation of cytotoxic T-cells in the tumor microenvironment (TME). We identify the HLA-I expression status of HRSC, found in a minority of HL, as a strong determinant of TME composition. Combined whole tissue and spatial analysis of the TME suggests the presence of a cytotoxic T-cell immune response in HLA-I positive HL. However, increased expression of the inhibitory immune-checkpoint LAG3 on CD8 + T-cells in close proximity to HRSC may interfere with the expected cytotoxicity leading to the observed absence of clonally expanded T-cells in HLA-I-positive HL. Of note, the observed effects were independent of the presence of Epstein-Barr Virus in HRSC. Moreover, HLA-I-positive HL are associated with a B-cell-rich TME and show a trend towards a favorable clinical course. In summary, our data suggest that HL with HLA-I + HRSC are distinct in their microenvironment and harbor traces of a cytotoxic immune response blocked by induction of LAG3 on CD8 + cells in proximity to HRSC. Given the major differences in TME composition immune checkpoint inhibitors may differ in their mechanism of action in HLA-I-positive compared to HLA-negative HL.