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In classical Hodgkin lymphoma (cHL), the highly abundant CD4+ T cells in the vicinity of tumor cells are considered essential for tumor cell survival, but are ill-defined. Although they are activated, they consistently lack expression of activation marker CD26. In this study, we compared sorted CD4+CD26- and CD4+CD26+ T cells from cHL lymph node cell suspensions by RNA sequencing and T cell receptor variable gene segment usage analysis. This revealed that although CD4+CD26- T cells are antigen experienced, they have not clonally expanded. This may well be explained by the expression of exhaustion associated transcription factors TOX and TOX2, immune checkpoints PDCD1 and CD200, and chemokine CXCL13, which were amongst the 100 significantly enriched genes in comparison with the CD4+CD26+ T cells. Findings were validated in single-cell RNA sequencing data from an independent cohort. Interestingly, immunohistochemistry revealed predominant and high frequency of staining for TOX and TOX2 in the T cells attached to the tumor cells. In conclusion, the dominant CD4+CD26- T cell population in cHL is antigen experienced, polyclonal, and exhausted. This population is likely a main contributor to the very high response rates to immune checkpoint inhibitors in cHL. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

Summary: Individually, tissue and soluble markers involved in the programmed cell death protein 1/programmed death‐ligand (PD‐1/PD‐L) axis have been described as biomarkers with clinical value in classical Hodgkin lymphoma (cHL). In the context of the success of immune checkpoint blockade therapy in cHL, it is interesting to discover whether plasma levels of proteins in the PD‐1/PD‐L axis are a reflection of expression by the corresponding tissue. Paired tissue and plasma samples of cHL patients were collected and analysed for PD‐1, PD‐L1 and PD‐L2 levels. In addition, vascular endothelial growth factor (VEGF) and CD83, molecules regarded to influence the expression of PD‐1, PD‐L1 and/or PD‐L2, were included. PD‐L1 was upregulated in the plasma of cHL patients compared to healthy controls and correlated well with several clinical parameters. Strong PD‐L1 expression in the tumour microenvironment contributed to high soluble (s)PD‐L1 levels, although there was no direct correlation between plasma PD‐L1 levels and total expression of PD‐L1 in corresponding cHL tissue. Interestingly, we observed a positive correlation between VEGF and PD‐1 levels in both tissue and plasma. In conclusion, although PD‐L1 is a promising soluble biomarker in cHL, its levels do not reflect the total tissue expression. Future studies focusing on PD‐L1 as a predictor for immune checkpoint treatment response, should include both biopsy and plasma samples. [ABSTRACT FROM AUTHOR]