Immune Biomarkers in the Peripheral Blood and Tumor Microenvironment of Classical Hodgkin Lymphoma Patients in Relation to Tumor Burden and Response to Treatment

Abstract

In classical Hodgkin lymphoma (cHL), the malignant cells represent only a small fraction of the tumor. Yet, they orchestrate a lymphocyte-dominated tumor microenvironment (TME) that supports their survival and growth. The systemic effects of this local immunomodulation are not fully elucidated. Here, we aimed at characterizing circulating lymphocytes and plasma proteins in relation to clinical parameters and treatment effect. Peripheral blood (PB) samples were obtained from 48 consecutive patients at diagnosis and at 2 time points after successful primary treatment. Single-cell suspensions were prepared from lymph node (LN) biopsies obtained for routine diagnostic purposes. Twenty healthy individuals were included as controls. Cells from PB and LN were analyzed by flow cytometry, and plasma proteins by Proximity Extension Assay. We found that the frequencies of T and B cells positively correlated between the LN and the PB compartments. Compared to controls, cHL patients had higher frequencies of proliferating T cells as well as higher expression of programmed death (PD)-1 and cytotoxic T lymphocyte antigen (CTLA)-4 in circulating T cells, and lower naive T-cell frequencies. Advanced-stage patients had fewer NK cells with a functionally impaired phenotype. Differences in the immune profile were observed in patients with a high tumor burden and with high inflammation, respectively. Most of these deviations disappeared after standard first-line treatment. Patients who received radiotherapy involving the mediastinum had low T-cell counts for a prolonged period. Our findings suggest that the immunomodulation of lymphocytes in the TME of cHL might affect immune biomarkers in the PB.

Clinical Prediction Dilemmas of Non-Diagnosed Nasopharyngeal Hodgkin Lymphoma

“…In patients compared to controls, larger percentages of CD4 + and CD8 + T cells expressed the inhibitory molecules PD-1 and CTLA-4, indicating that their T cells are exhausted. The proportions of CTLA-4 + CD4 + and CD8 + T cells as well as the fractions of PD-1 + CD8 + T cells reduced after standard-of-care first-line therapy [23] . Accordingly, it appears that anti-PD-1 therapy combined with chemotherapeutic agents [34] and anti-PD-1 monotherapy [22] in HL patients reverses T-cell exhaustion.…”

“…The latest study found that CHL patients displayed higher levels of proliferative T cells, higher concentrations of the circulating T cell markers, CTLA-4 and PD-1, and lower concentrations of naive T-cell frequencies in comparison to controls [23] .…”

“…Patients with HL, particularly those with CHL, frequently have lower absolute B cell counts in the tumor microenvironment [22] . In both early and advanced HL patients, Mulder et al discovered a significant decline in the absolute numbers of B cells [23] . Additionally, there was a significant negative correlation between the proportion of B cells in the peripheral blood and lymph nodes and the proportion of B cells in the lymph nodes was significantly lower in patients with high tumor burden.…”

“…Since CCL17 (also known as TARC) is a known and clinically useful biomarker for CHL, Mulder et al examined it by Enzyme Linked Immunosorbent Assay (ELISA) and anticipated to discover higher concentrations [23] . T helper 2 (Th2) CD4 + T cells that express the CCR4, the CCL17/TARC receptor, are specifically attracted by CCL17/TARC [31] .…”

Co-inhibition of adenosine 2b receptor and programmed death-ligand 1 promotes the recruitment and cytotoxicity of natural killer cells in oral squamous cell carcinoma

“…Currently, most of the immunomodulatory strategies for anti-cancer treatments focus on enhancing T-cell response ( Shimu et al, 2023 ). Moreover, abnormal expression of MHC I on tumor cells and upregulation of PD-L1 are associated with poor prognosis in Hodgkin lymphoma patients, thus suggesting that immune response is independent of T-cells, inhibited by PD-1, and rescued by PD-L1 blockade ( Mulder et al, 2022 ). Natural killer (NK) cells have cytolytic activity and are involved in the immune monitoring of tumor cells and virus-infected cells ( Peng et al, 2021 ).…”