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An anergic immune signature in the tumor microenvironment of classical Hodgkin lymphoma is associated with inferior outcome
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.ORCID iD: 0000-0002-0226-5681
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
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2018 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 100, no 1, p. 88-97Article in journal (Refereed) Published
Abstract [en]

Objective: The classical Hodgkin lymphoma (cHL) tumor microenvironment shows anongoing inflammatory response consisting of varying degrees of infiltrating eosinophils,mast cells, macrophages, regulatory T lymphocytes (Tregs), and activated lymphocytes surrounding the malignant cells. Herein, different immune signatures are characterized and correlated with treatment outcome.

Methods: Tumor-infiltrating leukocytes were phenotyped in biopsies from 459 patients with cHL. Time to progression (TTP) (primary progression, relapse, or death from cHL) and overall survival were analyzed using Cox proportional hazards regression.

Results: The leukocyte infiltration in the microenvironment was highly diverse between patients and was categorized in 4 immune signatures (active, anergic, innate, or mixed). A high proportion of Tregs (anergic) resulted in shorter TTP (median 12.9-year follow-up) in age-adjusted analyses (hazard ratio = 1.82; 95% confidence interval 1.05-3-15). Epstein-Barrvirus (EBV)-positive cases had higher proportions of macrophages and activated lymphocytes than EBV negative, but neither of those leukocytes predicted prognosis.

Conclusions: Abundant Tregs (anergic signature) indicate a shorter TTP, particularly in younger patients. This is probably due to a reduced ability of the immune system to attack the tumor cells. Our data warrant further investigation if these suggested immune signatures could predict outcome of immunotherapy such as immune checkpoint inhibitors.

Place, publisher, year, edition, pages
2018. Vol. 100, no 1, p. 88-97
Keyword [en]
Hodgkin lymphoma, Regulatory T lymphocytes, Tumor microenvironment
National Category
Cancer and Oncology
Research subject
Pathology; Oncology
Identifiers
URN: urn:nbn:se:uu:diva-335491DOI: 10.1111/ejh.12987ISI: 000418451500012PubMedID: 29064587OAI: oai:DiVA.org:uu-335491DiVA, id: diva2:1163123
Funder
Swedish Cancer Society, CAN 2016/440, CAN 2016/607, CAN 2016/552
Available from: 2017-12-06 Created: 2017-12-06 Last updated: 2018-01-29Bibliographically approved
In thesis
1. Epidemiology and prognosis in classical Hodgkin lymphoma
Open this publication in new window or tab >>Epidemiology and prognosis in classical Hodgkin lymphoma
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Classical Hodgkin lymphoma (HL) is a B cell derived neoplasm with an overall good prognosis. Its etiology and pathogenesis are largely unknown. The tumor microenvironment consists of sparse malignant cells and abundant leukocytes. In paper I we found that patients with rheumatoid arthritis (RA) had an increased risk of developing HL, especially patients with proxies of more severe RA. In addition, patients with RA had an especially increased risk of developing Epstein-Barr virus positive HL. These findings indicate that patients exposed to chronic inflammation have an increased risk of developing HL. We further studied the inflammatory milieu in the microenvironment of HL in paper II by investigating different leukocytes with immunohistochemical markers on diagnostic HL biopsies. We demonstrated that an anergic immune signature with a high amount of immune suppressive regulatory T lymphocytes was associated with inferior time to progression in an age-adjusted analysis. Another mechanism utilized by malignant cells and leukocytes to induce a suppressed antitumor immune response is to upregulate expression of programmed death ligands 1 and 2 (PD-L1 and PD-L2), that induces apoptosis in tumor killing leukocytes by binding to programmed death receptor 1 (PD-1). In paper III, we investigated the prognostic impact of PD-1, PD-L1 and PD-L2 in the tumor microenvironment of diagnostic HL biopsies with immunohistochemistry. We found that high proportions of PD-1+ and PD-L1+ leukocytes were associated with worse outcome in fully adjusted multivariate analyses. However, both PD-1 and PD-L1 are expressed to variable degrees in malignancies. Therefore, in paper IV we wanted to determine how expression of PD-1 and PD-L1 changes in repeated biopsies from both untreated and treated patients with relapsed HL. There were increased proportions of PD-1+ and PD-L1+ leukocytes, and PD-L1+ tumor cells in the relapse biopsies compared to the primary biopsies. These findings indicate that the PD-1 pathway is upregulated due to primary treatment, longer disease duration or altered conditions in the microenvironment at relapse.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 70
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1411
Keyword
Epstein-Barr virus, rheumatoid arthritis, tumor microenvironment, immunohistochemistry, immune checkpoints, regulatory T lymphocytes, PD-1, PD-L1
National Category
Cancer and Oncology
Research subject
Oncology; Pathology
Identifiers
urn:nbn:se:uu:diva-336026 (URN)978-91-513-0189-1 (ISBN)
Public defence
2018-02-14, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
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Available from: 2018-01-23 Created: 2017-12-12 Last updated: 2018-03-07

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