Th17 immune microenvironment in Epstein-Barr virus–negative Hodgkin lymphoma: implications for immunotherapy

Amy S. Duffield; Maria Libera Ascierto; Robert A. Anders; Janis M. Taube; Alan K. Meeker; Shuming Chen; Tracee L. McMiller; Neil A. Phillips; Haiying Xu; Aleksandra Ogurtsova; Alan E. Berger; Drew M. Pardoll; Suzanne L. Topalian; Richard F. Ambinder

Blood Advances (Jul 2017)

Th17 immune microenvironment in Epstein-Barr virus–negative Hodgkin lymphoma: implications for immunotherapy

Amy S. Duffield,
Maria Libera Ascierto,
Robert A. Anders,
Janis M. Taube,
Alan K. Meeker,
Shuming Chen,
Tracee L. McMiller,
Neil A. Phillips,
Haiying Xu,
Aleksandra Ogurtsova,
Alan E. Berger,
Drew M. Pardoll,
Suzanne L. Topalian,
Richard F. Ambinder

Affiliations

Amy S. Duffield: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD;; Bloomberg–Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and
Maria Libera Ascierto: Bloomberg–Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and; Department of Oncology,
Robert A. Anders: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD;; Bloomberg–Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and
Janis M. Taube: Bloomberg–Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and; Department of Dermatology,
Alan K. Meeker: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD;; Bloomberg–Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and
Shuming Chen: Bloomberg–Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and; Department of Surgery, and
Tracee L. McMiller: Bloomberg–Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and; Department of Surgery, and
Neil A. Phillips: Bloomberg–Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and; Department of Surgery, and
Haiying Xu: Bloomberg–Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and; Department of Dermatology,
Aleksandra Ogurtsova: Bloomberg–Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and; Department of Dermatology,
Alan E. Berger: Bloomberg–Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and; Department of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD
Drew M. Pardoll: Bloomberg–Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and; Department of Oncology,
Suzanne L. Topalian: Bloomberg–Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and; Department of Surgery, and; Suzanne L. Topalian, Johns Hopkins University School of Medicine, 1550 Orleans St, CRB2 Room 508, Baltimore, MD 21287;
Richard F. Ambinder: Bloomberg–Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and; Department of Oncology,; Richard F. Ambinder, Johns Hopkins University School of Medicine, 1650 Orleans St, CRB1 Room 389, Baltimore, MD 21287;

Journal volume & issue: Vol. 1, no. 17
pp. 1324 – 1334

Abstract

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Abstract: Classical Hodgkin lymphoma (CHL) is a neoplasm characterized by robust inflammatory infiltrates and heightened expression of the immunosuppressive PD-1/PD-L1 pathway. Although anti-PD-1 therapy can be effective in >60% of patients with refractory CHL, improved treatment options are needed for CHLs which are resistant to anti-PD-1 or relapse after this form of immunotherapy. A deeper understanding of immunologic factors in the CHL microenvironment might support the design of more effective treatment combinations based on anti-PD-1. In addition, because the Epstein-Barr virus (EBV) residing in some CHL tumors is strongly immunogenic, we hypothesized that characteristics of the tumor immune microenvironment in EBV+ CHL would be distinct from EBV− CHL, with specific implications for designing combination treatment regimens. Employing immunohistochemistry for immune cell subsets and checkpoint molecules, as well as gene expression profiling, we characterized 32 CHLs from the Johns Hopkins archives, including 12 EBV+ and 20 EBV− tumors. Our results revealed a dichotomous cellular and cytokine immune milieu in EBV+ vs EBV− CHL. EBV+ tumors displayed a T helper 1 (Th1) profile typical of effective antitumor immunity, with increased infiltration of CD8+ T cells and coordinate expression of the canonical Th1 transcription factor Tbet (TBX21), interferon-γ (IFNG), and the IFN-γ–inducible immunosuppressive enzyme indoleamine 2,3-dioxygenase. In contrast, EBV− tumors manifested a pathogenic Th17 profile and ongoing engagement of the interleukin-23 (IL-23)/IL-17 axis, with heightened phosphorylated signal transducer and activator of transcription 3 expression in infiltrating lymphocytes. These findings suggest that drugs blocking the IL-23/IL-17 axis, which are already in the clinic for treating certain autoimmune disorders, may enhance the therapeutic impact of anti-PD-1 therapy in EBV− CHL.

Published in Blood Advances

ISSN: 2473-9529 (Print); 2473-9537 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine
Website: https://ashpublications.org/bloodadvances

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