| 1. |
- Gholiha, Alex R., et al.
(author)
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High tumour plasma cell infiltration reflects an important microenvironmental component in classic Hodgkin lymphoma linked to presence of B-symptoms
- 2019
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In: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 184:2, s. 192-201
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Journal article (peer-reviewed)abstract
- Plasma cells are important prognostic actors in different malignancies. The tumour microenvironmental composition in classic Hodgkin lymphoma (cHL) is a major prognostic key element; however, clinicopathological studies regarding plasma cells in cHL are lacking. The aim of this study was to investigate CD138+ (also termed SDC1+) plasma cell and IgG4 producing (IgG4+) plasma cells infiltration in the microenvironment of cHL. Immunohistochemistry with anti-CD138 and IgG4 antibodies was performed on diagnostic tumour biopsies from 124 patients with cHL, on tissue micro array (TMA). In 120 cases, CD138+ plasma cell-infiltration was associated with the presence of B-symptoms (P = 0·028) and advanced stage, IIB-IVB (P = 0·009). In multivariate analysis, CD138+ plasma cells correlated with eosinophil infiltration (P = 0·013). The subgroup of IgG4+ plasma cells was analysed in 122 cases and only correlated to CD138+ plasma cells (P = 0·004). Patients with high proportion of tumour infiltrating CD138+ plasma cells (defined as ≥10%), had a more inferior event-free survival (P = 0·007) and overall survival (P = 0·004) than patients with a low proportion of infiltrating CD138+ plasma cells (<10%), although significance was not maintained in multivariate analysis. In summary, a high proportion of tumour-associated plasma cells in cHL reflect an important component in the microenvironment of cHL.
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| 2. |
- Gholiha, Alex R., et al.
(author)
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Immune-Proteome Profiling in Classical Hodgkin Lymphoma Tumor Diagnostic Tissue
- 2022
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In: Cancers. - : MDPI. - 2072-6694. ; 14:1
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Journal article (peer-reviewed)abstract
- In classical Hodgkin Lymphoma (cHL), immunoediting via protein signaling is key to evading tumor surveillance. We aimed to identify immune-related proteins that distinguish diagnostic cHL tissues (=diagnostic tumor lysates, n = 27) from control tissues (reactive lymph node lysates, n = 30). Further, we correlated our findings with the proteome plasma profile between cHL patients (n = 26) and healthy controls (n = 27). We used the proximity extension assay (PEA) with the OlinkTM multiplex Immuno-Oncology panel, consisting of 92 proteins. Univariate, multivariate-adjusted analysis and Benjamini–Hochberg’s false discovery testing (=Padj) were performed to detect significant discrepancies. Proteins distinguishing cHL cases from controls were more numerous in plasma (30 proteins) than tissue (17 proteins), all Padj < 0.05. Eight of the identified proteins in cHL tissue (PD-L1, IL-6, CCL17, CCL3, IL-13, MMP12, TNFRS4, and LAG3) were elevated in both cHL tissues and cHL plasma compared with control samples. Six proteins distinguishing cHL tissues from controls tissues were significantly correlated to PD-L1 expression in cHL tissue (IL-6, MCP-2, CCL3, CCL4, GZMB, and IFN-gamma, all p ≤0.05). In conclusion, this study introduces a distinguishing proteomic profile in cHL tissue and potential immune-related markers of pathophysiological relevance
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| 3. |
- Gholiha, Alex R.
(author)
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Immunologic Markers in the Tumor Microenvironment of Classical Hodgkin Lymphoma
- 2021
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Doctoral thesis (other academic/artistic)abstract
- In classical Hodgkin lymphoma (cHL), cytokine regulation and cellular composition of the tumor microenvironment (TME) is crucial for tumor cell survival. In paper I, we examined the presence of CD138+ plasma cells and IgG4+ plasma cells in diagnostic cHL biopsies with immunohistochemistry (IHC). We found that increasing proportions of CD138+ plasma cells in the TME were associated with B-symptoms and inferior survival. IgG4+ plasma cells in the TME were a rare finding. In paper II, we investigated IL-6+ leukocytes and IL-6+ Hodgkin-Reed-Sternberg (HRS) cells in the TME of primary cHL. We observed that an IL-6+ leukocyte proportion of ≤ 1% in the TME was an independent adverse prognostic marker for event-free and overall survival. Further, the presence of IL-6+ leukocytes correlated with an increased proportion of CD138+ plasma cells and CD68+macrophages in the TME. IL-6+ HRS cells correlated with increased proportions of CD68+macrophages, PD-L1+ leukocytes, and PD-L1+HRS cells. In paper III, we investigated CD47 surface glycoprotein expression on HRS cells in the TME. CD47 is mainly known to promote antiphagocytic signaling via interaction with the SIRPa protein on phagocytic cells. IHC for CD47 was performed on diagnostic cHL biopsies. Cases with high CD47 expression on HRS cells had an inferior survival in univariate and multivariate analyses, adjusting for established prognostic factors compared with patients with low CD47 expression on HRS cells. In paper IV, using the Proximity Extension Assay (PEA) method, we identified 17 distinguishing immunologic proteins in cHL when comparing cHL diagnostic tissue lysates with reactive lymph node lysates from controls. In addition, 8 of these 17 proteins were elevated in cHL plasma compared with plasma from controls. Several of the identified proteins have established evidence in cHL as PD-L1, IL-6, CCL17, LAG3, and several proteins were introduced as new potential targets. In conclusion, our findings increase our knowledge regarding several immunological elements within the TME of cHL introducing clinicopathological associations of prognostic and potential therapeutic future implications.
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| 4. |
- Gholiha, Alex R., et al.
(author)
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Revisiting IL-6 expression in the tumor microenvironment of classical Hodgkin lymphoma
- 2021
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In: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 5:6, s. 1671-1681
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Journal article (peer-reviewed)abstract
- Interleukin-6 (IL-6) can induce therapeutic resistance for several cancer agents currently used to treat classical Hodgkin lymphoma (cHL). We aimed to investigate whether the presence of IL-6(+) leukocytes and IL-6(+) Hodgkin-Reed-Sternberg (HRS) cells in the tumor microenvironment (TME) was associated with adverse survival outcomes, expression of other immune markers, and serum IL-6 levels. We used a contemporarily treated cohort (n = 136), with a median follow-up of 13.8 years (range, 0.59-15.9 years). We performed immunohistochemistry with an IL-6 antibody on tissue microarrays from diagnostic biopsies of cHL patients. Patients with IL-6(+) leukocytes >= 1% (n = 54 of 136) had inferior event-free survival (hazard ratio [HR] = 3.58; 95% confidence interval [CI], 1.80-7.15) and overall survival (HR = 6.71; 95% CI, 2.51-17.99). The adverse survival was maintained in multivariate Cox regression and propensity score-matched analyses, adjusting for well-known poor-prognostic covariates. The presence of IL-6(+) HRS cells and high serum IL-6 levels were not associated with survival. IL-6(+) leukocytes correlated with increased proportions of IL-6(+) HRS cells (P < .01), CD138(+) plasma cells (P < .01), CD68(+) macrophages (P = .02), and tryptase-positive mast cells (P < .01). IL-6(+) HRS cells correlated with increased proportions of CD68+ macrophages (P = .03), programmed death-ligand 1-positive (PD-L1(+)) leukocytes (P = .04), and PD-L1(+) HRS cells (P < .01). Serum-IL-6 lacked correlation with IL-6 expression in the TME. This is the first study highlighting the adverse prognostic impact of IL-6(+) leukocytes in the TME in a cohort of contemporarily treated adult patients with cHL.
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| 5. |
- Persson Skare, Tor, et al.
(author)
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Marginal zone lymphoma expression of histidine-rich glycoprotein correlates with improved survival
- 2020
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In: eJHaem. - : Wiley. - 2688-6146. ; 1:1, s. 199-207
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Journal article (peer-reviewed)abstract
- The abundant hepatocyte-expressed plasma protein histidine-rich glycoprotein (HRG) enhances antitumor immunity by polarizing inflammatory and immune cells in several mouse models, however, the clinical relevance of HRG in human cancer is poorly explored. The expression and role of HRG in human B-cell lymphomas was investigated in order to find new tools for prognosis and treatment. Findings Immunohistochemical (IHC) analysis and RNA hybridization of tissue microarrays showed that (i) HRG was expressed by tumor cells in marginal zone lymphoma (MZL), in 36% of 59 cases. Expression was also detected in follicular lymphoma (22%), mantle cell lymphoma (19%), and indiffuse large B-cell lymphoma (DLBCL;5%) while primary CNS lymphoma (PCNSL) lacked expression of HRG. (ii) MZL patients positive for HRG showed a superior overall survival outcome (HR = 0.086, 95% CI = 0.014-0.518, P-value = .007), indicating a protective role for HRG independent of stage, age and sex. (iii) HRG-expressing MZL displayed significantly increased transcript and protein levels of the host defense peptide alpha defensin 1. In addition, global transcript analyses showed significant changes in gene ontology terms relating to immunity and inflammation, however, infiltration of immune and inflammatory cells detected by IHC was unaffected by HRG expression. Conclusion HRG expression by MZL tumor cells correlates with an altered transcription profile and improved overall survival.
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