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Hodgkin lymphoma (HL) is a common malignancy in young adults. It is characterized by a minority of tumor cells surrounded by an abundant inflammatory infiltrate, which mainly consists of CD4+ T cells. The current treatment strategy has a high cure-rate, but often results in long-term treatment related adverse events. Therefore, new treatment options such as immune checkpoint blockade (ICB) are being explored. In this project we characterized CD4+ T cells and their interactions with tumor cells, with a specific focus on the role of CD4+ T cells in ICB therapy. We discovered that CD4+ T cells are weakly activated by T cell receptor (TCR)-HLA class II and CD2-CD58 interactions with the tumor cells. These T cells that are in close proximity to the tumor cells have been activated before (antigen experienced) and are diverse (polyclonal). In addition, they specifically express transcription factors TOX and TOX2 that are associated with T cell exhaustion and can be induced by chronic or repeated TCR stimulation. This suggests that Hodgkin tumor cells actively inhibit cells in their surrounding to promote tumor cell survival. We developed a long-term co-culture model and found that blocking PD-1 with nivolumab results in pronounced CD4+ T cell activation and proliferation, confirming the potential of this treatment in HL. In addition, we identified soluble PD-L1 as a promising biomarker in HL patients. In summary, our studies provide novel insights into the function of CD4+ T cells in HL biology and treatment responses. This may help improve immunotherapy in HL patients.

High programmed cell death 1 ligand 1 (PD-L1) protein expression and copy number alterations (CNAs) of the corresponding genomic locus 9p24.1 in Hodgkin- and Reed-Sternberg cells (HRSC) have been shown to be associated with favourable response to anti-PD-1 checkpoint inhibition in relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). In the present study, we investigated baseline 9p24.1 status as well as PD-L1 and major histocompatibility complex (MHC) class I and II protein expression in 82 biopsies from patients with early stage unfavourable cHL treated with anti-PD-1-based first-line treatment in the German Hodgkin Study Group (GHSG) NIVAHL trial (ClinicalTrials.gov Identifier: NCT03004833). All evaluated specimens showed 9p24.1 CNA in HRSC to some extent, but with high intratumoral heterogeneity and an overall smaller range of alterations than reported in advanced-stage or r/r cHL. All but two cases (97%) showed PD-L1 expression by the tumour cells in variable amounts. While MHC-I was rarely expressed in >50% of HRSC, MHC-II expression in >50% of HRSC was found more frequently. No obvious impact of 9p24.1 CNA or PD-L1 and MHC-I/II expression on early response to the highly effective anti-PD-1-based NIVAHL first-line treatment was observed. Further studies evaluating an expanded panel of potential biomarkers are needed to optimally stratify anti-PD-1 first-line cHL treatment.