Defining characteristics of classical Hodgkin lymphoma microenvironment T-helper cells

Abstract

Key Points• Hodgkin lymphoma microenvironment T-helper cells express TH1/activation markers and lack TH2/ immunosuppression markers.• These cells are functional, retaining the capacity for cytokine secretion and proliferation in vitro. CD41 T-helper cells (THs) dominate the classical Hodgkin lymphoma (CHL) microenvironment, but their role is poorly understood. Advances in flow cytometry and immunohistochemistry permit more detailed investigation of this aspect of CHL pathophysiology. To address the hypothesis that the TH-infiltrate, rather than being TH2-enriched, senescent and hypofunctional, is TH1 and activation marker-rich, cytokine-secretory and proliferative, we applied comprehensive flow cytometric immunophenotyping and functional assays of cytokine secretion/proliferation to TH cells from 18 CHL-derived single-cell suspensions (SCSs) compared to reactive lymph nodes (RLNs). CHL-derived TH cells express TH1-associated CXCR3/CCR5 and TNFa/IFNg/interleukin-2 (IL-2) and less TH2-associated CCR3/ CCR4, with no IL-4/IL-13. They lack exhaustion-/suppression-associated PD1, CD57 and terminally differentiated effector memory cells, with more central memory cells, activationassociated partners of Hodgkin Reed Sternberg (HRS) cell-expressed CD30/OX40-L/ICOS-L, and other activation markers. TH cell lines established from CHL and RLN-derived SCSs remain cytokine-secretory. We confirmed and extended these studies using tissue microarray immunohistochemistry (TMA-IHC) from a large CHL tissue bank (n = 122) and demonstrate TH1-associated TBET is abundant in CHL, and TH2-associated CMAF/GATA3 and exhaustion-associated PD1 expressed at significantly lower levels. These molecular insights into the CHL-associated TH offer potential diagnostic, prognostic and pharmacologically modifiable therapeutic targets and do not support the established view of a TH2-enriched, senescent/exhausted, hypofunctional, hypoproliferative infiltrate.

The emerging role of immune checkpoint inhibition in malignant lymphoma

“…25 In another immunohistochemical study, PD-1 expression on tumorinfiltrating lymphocytes was suggested as a stage-independent negative prognostic factor for overall survival (OS) in cHL, 26 while others found only rare PD-1-positive tumor-infiltrating lymphocytes. 27 According to two phase I trials investigating the safety and activity of anti-PD1 antibodies in r/r HL, over 90% of the examined patients' samples showed strong expression of PD-L1 on HRS cells, with rather low PD-1 expression on tumor-infiltrating lymphocytes. 18,28 Taking these discrepant data into account, relevant predictive factors for treatment outcome with anti-PD1 antibodies are still unknown.…”

The immune microenvironment in Hodgkin lymphoma: T cells, B cells, and immune checkpoints

“…44 Mechanistically, T cells in CHL can promote RS cell survival and proliferation via CD40/CD40 ligand-mediated alternative activation of NF-kB; 45 this growth signal may be particularly important for the survival of RS cells, which have lost the ability to activate NF-kB through conventional B cell receptor-driven signals. [46][47][48] The multiple mechanisms by which RS cells and the CHL microenvironment suppress immune responses are summarized in Figure 1; therapies aimed at breaking this pathological cycle of T cell fueled growth and immune evasion, primarily via checkpoint blockade, are discussed below.…”

A novel immunohistochemical classifier to distinguish Hodgkin lymphoma from ALK anaplastic large cell lymphoma

“…43,44 However, it could recently be shown that the majority of T cells in classical Hodgkin lymphoma microenvironment represents TH 1 cells. 45 In conclusion, three of four genes overexpressed in the Hodgkin and Reed-Sternberg cells in comparison with the tumor cells of ALK À anaplastic large cell lymphoma are also expressed in antigenpresenting cells and are related to the interactions between Hodgkin and Reed-Sternberg cells and surrounding T cells. Moreover, Hodgkin and Reed-Sternberg cells are known to express several additional markers usually expressed by antigenpresenting cells.…”