Human leukocyte antigen (HLA) class I expression on Hodgkin-Reed-Sternberg cells is an EBV-independent major determinant of microenvironment composition in classic Hodgkin lymphoma.

Hodgkin-Reed-Sternberg cells (HRSCs) in classic Hodgkin Lymphoma (HL) frequently lack expression of human leukocyte antigen class I (HLA-I), considered to hamper activation of cytotoxic T cells in the tumor microenvironment (TME). Here, we demonstrate HLA-I expression on HRSCs to be a strong determinant of TME composition whereas expression of HLA-II was associated with only minor differential gene expression in the TME. In HLA-I-positive HL the HRSC content and expression of CCL17/TARC in HRSCs are low, independent of the presence of Epstein-Barr virus in HRSCs. Additionally, HLA-I-positive HL shows a high content of CD8+ cytotoxic T cells. However, an increased expression of the inhibitory immune checkpoint LAG3 on CD8+ T cells in close proximity to HRSCs is observed. Suggesting interference with cytotoxic activity, we observed an absence of clonally expanded T cells in the TME. While HLA-I-positive HL is not associated with an unfavorable clinical course in our cohorts, they share features with the recently described H2 subtype of HL. Given the major differences in TME composition, immune checkpoint inhibitors may differ in their mechanism of action in HLA-I-positive compared to HLA-I-negative HL.