title: Defining characteristics of classical Hodgkin lymphoma microenvironment T-helper cells.
abstract: CD4(+) 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 TNFα/IFNγ/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, activation-associated 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.
authors.affiliation: Centre for Haemato-oncology, Bart's Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Greaves
authors.forename: Andrew
authors.initials: A
authors.lastname: Clear
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
authors.forename: Sameena
authors.initials: S
authors.lastname: Iqbal
authors.forename: Abigail
authors.initials: A
authors.lastname: Lee
authors.forename: Janet
authors.initials: J
authors.lastname: Matthews
authors.forename: Andrew
authors.initials: A
authors.lastname: Wilson
authors.forename: Maria
authors.initials: M
authors.lastname: Calaminici
authors.forename: John G
authors.initials: JG
authors.lastname: Gribben
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D049109:Cell Proliferation; D016922:Cellular Senescence; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006689:Hodgkin Disease / Q000097:blood*; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000378:metabolism*; D016896:Treatment Outcome; D059016:Tumor Microenvironment; D055815:Young Adult
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents