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Epidemiology and prognosis in classical Hodgkin lymphoma
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. (Gunilla Enblad)ORCID iD: 0000-0002-0226-5681
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
Keywords [en]
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: urn:nbn:se:uu:diva-336026ISBN: 978-91-513-0189-1 (print)OAI: oai:DiVA.org:uu-336026DiVA, id: diva2:1164819
Public defence
2018-02-14, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2018-01-23 Created: 2017-12-12 Last updated: 2018-03-07
List of papers
1. Autoimmune and Atopic Disorders and Risk of Classical Hodgkin Lymphoma
Open this publication in new window or tab >>Autoimmune and Atopic Disorders and Risk of Classical Hodgkin Lymphoma
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2015 (English)In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 182, no 7, p. 624-632Article in journal (Refereed) Published
Abstract [en]

Results from previous investigations have shown associations between the risk of Hodgkin lymphoma (HL) and a history of autoimmune and atopic diseases, but it remains unknown whether these associations apply to all types of HL or only to specific subtypes. We investigated immune diseases and the risk of classical HL in a population-based case-control study that included 585 patients and 3,187 controls recruited from October 1999 through August 2002. We collected information on immune diseases through telephone interviews and performed serological analyses of specific immunoglobulin E reactivity. Tumor Epstein-Barr virus (EBV) status was determined for 498 patients. Odds ratios with 95% confidence intervals were calculated using logistic regression analysis. Rheumatoid arthritis was associated with a higher risk of HL (odds ratio (OR) = 2.63; 95% confidence interval (CI): 1.47, 4.70), especially EBV-positive HL (OR = 3.18; 95% CI: 1.23, 8.17), and with mixed-cellularity HL (OR = 4.25; 95% CI: 1.66, 10.90). HL risk was higher when we used proxies of severe rheumatoid arthritis, such as ever having received daily rheumatoid arthritis medication (OR = 3.98; 95% CI: 2.08, 7.62), rheumatoid arthritis duration of 6-20 years (OR = 3.80; 95% CI: 1.72, 8.41), or ever having been hospitalized for rheumatoid arthritis (OR = 7.36; 95% CI: 2.95, 18.38). Atopic diseases were not associated with the risk of HL. EBV replication induced by chronic inflammation in patients with autoimmune diseases might explain the higher risk of EBV-positive HL.

Keywords
atopic hypersensitivity, Epstein-Barr virus, Hodgkin lymphoma, primary Sjogren's syndrome, rheumatoid arthritis, systemic lupus erythematosus
National Category
Public Health, Global Health, Social Medicine and Epidemiology Occupational Health and Environmental Health
Identifiers
urn:nbn:se:uu:diva-264812 (URN)10.1093/aje/kwv081 (DOI)000361811100009 ()26346543 (PubMedID)
Funder
NIH (National Institute of Health), 5 ROI CA-69269Swedish Society of MedicineSwedish Society for Medical Research (SSMF)
Available from: 2015-11-02 Created: 2015-10-19 Last updated: 2018-01-10Bibliographically approved
2. An anergic immune signature in the tumor microenvironment of classical Hodgkin lymphoma is associated with inferior outcome
Open this publication in new window or tab >>An anergic immune signature in the tumor microenvironment of classical Hodgkin lymphoma is associated with inferior outcome
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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.

Keywords
Hodgkin lymphoma, Regulatory T lymphocytes, Tumor microenvironment
National Category
Cancer and Oncology
Research subject
Pathology; Oncology
Identifiers
urn:nbn:se:uu:diva-335491 (URN)10.1111/ejh.12987 (DOI)000418451500012 ()29064587 (PubMedID)
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
3. High proportions of PD-1+ and PD-L1+ leukocytes in classical Hodgkin lymphoma microenvironment are associated with inferior outcome
Open this publication in new window or tab >>High proportions of PD-1+ and PD-L1+ leukocytes in classical Hodgkin lymphoma microenvironment are associated with inferior outcome
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2017 (English)In: Blood Advances, ISSN 2473-9529, Vol. 1, no 18, p. 1427-1439Article in journal (Refereed) Published
Abstract [en]

Immune checkpoint inhibition targeting the programmed death receptor (PD)-1 pathway is a novel treatment approach in relapsed and refractory classical Hodgkin lymphoma (cHL). Identifying patients with a high risk of treatment failure could support the use of PD-1 inhibitors as front-line treatment. Our aim was to investigate the prognostic impact of PD-1, programmed death-ligand 1 (PD-L1), and PD-L2 in the tumor microenvironment in diagnostic biopsies of patients with cHL. Patients from Denmark and Sweden, diagnosed between 1990 and 2007 and ages 15 to 86 years, were included. Tissue microarray samples were available from 387 patients. Immunohistochemistry was used to detect PD-1, PD-L1, and PD-L2, and the proportions of positive cells were calculated. Event-free survival (EFS; time to treatment failure) and overall survival (OS) were analyzed using Cox proportional hazards regression. High proportions of both PD-1(+) (hazard ratio [HR], 1.77; 95% confidence interval [CI], 1.10-2.86) and PD-L1(+) (HR 5 1.89; 95% CI, 1.08-3.30) leukocytes in the microenvironment were associated with inferior EFS in a multivariate analysis (adjusted for white blood cell count >15 x 10(9)/L, hemoglobin <105 g/L, albumin <40 g/L, B symptoms, extranodal involvement, stage, bulky tumor, nodular sclerosis subtype, Epstein-Barr virus status, lymphocyte count <0.6 x 10(9)/L, sex, and country). A high proportion of PD-L1(+) leukocytes was also associated with inferior OS in a multivariate analysis (HR, 3.46; 95% CI, 1.15-10.37). This is the first study to show a correlation after multivariate analysis between inferior outcome in cHL and a high proportion of both PD-1(+) and PD-L1(+) leukocytes in the tumor microenvironment.

National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-332667 (URN)10.1182/bloodadvances.2017006346 (DOI)000407339200010 ()
Funder
Swedish Cancer Society, CAN2016/440
Available from: 2017-10-31 Created: 2017-10-31 Last updated: 2017-12-19Bibliographically approved
4. PD-1 and PD-L1 are upregulated in paired consecutive biopsies with classical Hodgkin lymphoma
Open this publication in new window or tab >>PD-1 and PD-L1 are upregulated in paired consecutive biopsies with classical Hodgkin lymphoma
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: High proportions of programmed death receptor 1 (PD-1) and its ligand (PD-L1) in the microenvironment of primary classical Hodgkin lymphoma (cHL) are associated with inferior outcome. However, it is unclear how expression alter during disease progression and if treatment and a subsequent relapse affect their expression. Our aim was to study the heterogeneity of PD-1 and PD-L1 in paired biopsies from untreated and treated cHL patients

Patients and methods: Patients with multiple biopsies with cHL were identified from three Swedish pathology departments. Eleven patients had a paired diagnostic cHL biopsy and a previous benign lymph node biopsy, which during our review were reclassified as cHL, designated as the untreated group. Thirty patients had a paired primary and a relapse biopsy, designated as the treated group. Cases were immunostained to detect PD-1+ and PD-L1+ leukocytes, and PD-L1+ Hodgkin and Reed-Sternberg (HRS) cells. Differences in expression between biopsies were tested using Wilcoxon signed rank test.

Results: In the untreated group, 8 of 11 cases (73%) showed an increased proportion of PD-L1+ leukocytes in biopsy 2 compared to biopsy 1, while none of the markers were statistically significantly different when biopsy 1 and 2 were compared. In the treated group, 19 of 30 (63%), 22 of 30 (73%), and 18 of 30 (60%) cases showed increased proportions of PD-1+ leukocytes, PD-L1+ leukocytes and PD-L1+ HRS cells, respectively. When the primary and the relapse biopsies were compared, PD-1+ leukocytes (p=0.04), PD-L1+ leukocytes (p=0.005) and PD-L1+ HRS cells (p=0.009) were statistically significantly different.   

Conclusion: Our findings indicate that PD-1 and PD-L1 increase both due to longer disease duration and following treatment in relapsed cHL.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-336018 (URN)
Available from: 2017-12-11 Created: 2017-12-11 Last updated: 2017-12-14Bibliographically approved

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