Immunologic Markers in the Tumor Microenvironment of Classical Hodgkin Lymphoma

Abstract: In classical Hodgkin lymphoma (cHL), cytokine regulation and cellular composition of the tumor microenvironment (TME) is crucial for tumor cell survival. In paper I, we examined the presence of CD138+ plasma cells and IgG4+ plasma cells in diagnostic cHL biopsies with immunohistochemistry (IHC). We found that increasing proportions of CD138+ plasma cells in the TME were associated with B-symptoms and inferior survival. IgG4+ plasma cells in the TME were a rare finding. In paper II, we investigated IL-6+ leukocytes and IL-6+ Hodgkin-Reed-Sternberg (HRS) cells in the TME of primary cHL. We observed that an IL-6+ leukocyte proportion of ≤ 1% in the TME was an independent adverse prognostic marker for event-free and overall survival. Further, the presence of IL-6+ leukocytes correlated with an increased proportion of CD138+ plasma cells and CD68+macrophages in the TME. IL-6+ HRS cells correlated with increased proportions of CD68+macrophages, PD-L1+ leukocytes, and PD-L1+HRS cells. In paper III, we investigated CD47 surface glycoprotein expression on HRS cells in the TME. CD47 is mainly known to promote antiphagocytic signaling via interaction with the SIRPa protein on phagocytic cells. IHC for CD47 was performed on diagnostic cHL biopsies. Cases with high CD47 expression on HRS cells had an inferior survival in univariate and multivariate analyses, adjusting for established prognostic factors compared with patients with low CD47 expression on HRS cells. In paper IV, using the Proximity Extension Assay (PEA) method, we identified 17 distinguishing immunologic proteins in cHL when comparing cHL diagnostic tissue lysates with reactive lymph node lysates from controls. In addition, 8 of these 17 proteins were elevated in cHL plasma compared with plasma from controls. Several of the identified proteins have established evidence in cHL as PD-L1, IL-6, CCL17, LAG3, and several proteins were introduced as new potential targets. In conclusion, our findings increase our knowledge regarding several immunological elements within the TME of cHL introducing clinicopathological associations of prognostic and potential therapeutic future implications.