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- Mitteldorf, C., et al.
(author)
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Tumor Microenvironment and Checkpoint Molecules in Primary Cutaneous Diffuse Large B-Cell Lymphoma - New Therapeutic Targets
- 2017
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In: American Journal of Surgical Pathology. - : Lippincott Williams and Wilkins. - 0147-5185 .- 1532-0979. ; 41:7, s. 998-1004
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Journal article (peer-reviewed)abstract
- Programmed death ligand 1 (PD-L1) is expressed by 20% to 57% of systemic diffuse large B cell lymphomas (DLBCLs). PD-L1 expression in primary cutaneous DLBCL (pcDLBCL) has not been studied so far. Sixteen paraffin-embedded tissue samples of pcDLBCL (13 leg type [LT], 3 others [OT]) were investigated for PD-1, PD-L1, and CD33 expression and the cellular composition of the tumor microenvironment, focusing on myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages. Membrane-bound PD-L1 expression by the tumor cells was observed in all samples, albeit to a variable extent (19.9%). As expected, most DLBCL-LT (10 cases) were classified as activated B cell like type, with a higher PD-L1 score (21.9%) compared with that of the germinal center B cell like type (7.7%). The surrounding infiltrate consisted predominately of CD163(+) M2 rather than CD68(+) macrophages (CD68:CD163=1:4 to 6). Moreover, a considerable proportion of CD33(+) MDSCs with PD-L1 coexpression was admixed. Tumor cells expressed CD33 to variable degrees (2% to 60%). The number of MDSCs or M2 macrophages did not correlate with pcDLBCL subtypes LT or OT. T cells were only a minor component of the tumor microenvironment. We propose that PD-L1(+) tumor cells and PD-L1(+) MDSCs shield the tumor against PD-1(+) tumor-infiltrating lymphocytes, consequently leading to inhibition and diminution of tumor-infiltrating lymphocytes. Moreover, we found a polarization to M2 macrophages, which may contribute to the poor prognosis of DLBCL patients. Thus, targeting of tumor cells and MDSCs using anti-PD-1/anti-PD-L1 or anti-CD33 antibodies might be a worthwhile new approach to treat this aggressive form of cutaneous B-cell lymphoma. © 2017 Wolters Kluwer Health, Inc. All rights reserved.
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| 3. |
- Mitteldorf, C., et al.
(author)
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Expression of programmed death-1 (CD279) in primary cutaneous B-cell lymphomas with correlation to lymphoma entities and biological behaviour
- 2013
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In: British Journal of Dermatology. - : Blackwell Publishing Ltd. - 0007-0963 .- 1365-2133. ; 169:6, s. 1212-1218
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Journal article (peer-reviewed)abstract
- Background Programmed death-1 (PD-1/CD279) is a cell-surface protein expressed in activated T cells and a subset of T lymphocytes including follicular helper T cells (TFH). The interaction between PD-1 and its ligands plays a role in immune response and evasion of malignancies. In nodal follicular lymphoma, the number of intratumoral PD-1-positive lymphocytes is associated with overall survival. Objectives To investigate 28 cases of primary cutaneous B-cell lymphoma, including the subtypes PCFCL (n = 10), PCMZL (n = 10) and DLBCL-LT (n = 8) for the number and density of PD-1-positive cells. Methods Immunohistochemical staining and a computerized morphometric analysis for evaluation were applied. The results were correlated with the clinical outcome. To distinguish between activated T cells and TFH we performed PD-1/bcl-6 double staining and compared these results with CXCL-13 staining. Double staining for PD-1 and PAX-5 was used to investigate whether tumour cells were positive for PD-1. Results The PD-1-positive cells represented tumour-infiltrating T cells (TILs). Only a minor subset was represented by TFH. Patients with DLBCL-LT had a significantly lower number of PD-1-positive TILs than those with PCMZL (P = 0·012) and PCFCL (P = 0·002) or both (P = 0·001). The difference between PCMZL and PCFCL did not reach significance (P = 0·074). The tumour cells were negative for PD-1. Conclusions A higher number of PD-1-expressing cells was found in indolent PCMZL and PCFCL than in high-malignant DLBCL-LT. The PD-1-positive cells represented not only TFH, but also other activated T cells as a part of the tumour microenvironment. The tumour cells in all investigated types of PCBCL did not show aberrant PD-1 expression. What’s already known about this topic? In nodal follicular lymphoma, the number of intratumoral programmed death (PD)-1-positive lymphocytes is associated with overall survival. No data exist for primary cutaneous B-cell lymphoma (PCBCL). What does this study add? A higher number of PD-1-expressing cells was found in indolent primary cutaneous marginal zone lymphoma and primary cutaneous follicle centre lymphoma, in contrast to the more aggressive diffuse large B-cell lymphoma, leg type. PD-1-positive cells do not represent only follicular helper T cells. The tumour cells in all investigated types of PCBCL did not show aberrant PD-1 expression. © 2013 British Association of Dermatologists.
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- Mitteldorf, C., et al.
(author)
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Galectin-3 Expression in Primary Cutaneous CD30-Positive Lymphoproliferative Disorders and Transformed Mycosis Fungoides
- 2015
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In: Dermatology. - : S. Karger AG. - 1018-8665 .- 1421-9832. ; 231:2, s. 164-170
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Journal article (peer-reviewed)abstract
- Background: In nodal anaplastic large cell lymphoma, strong expression of galectin-3 (Gal-3) has been found, but only very few cases of primary cutaneous lymphoma have so far been examined. Objectives: To investigate 11 primary cutaneous anaplastic large cell lymphomas (PCALCL), 47 lymphomatoid papuloses (LYP) and 14 cases of transformed mycosis fungoides with CD30 expression (MF-T) for Gal-3 expression. Methods: A Gal-3 score was applied using a photo-based morphometric evaluation program. Double staining for CD30 and Gal-3 was performed. Furthermore, we recorded the cellular and extracellular sublocalization of the signal. Results: The Gal-3 expression in CD30+ tumor cells was significantly lower in MF-T in contrast to CD30+ lymphoproliferative disorders (CD30 LPD; p < 0.001), but we found no differences between PCALCL and LYP (p = 0.42). In PCALCL Gal-3 was more often localized in the cytoplasm in contrast to LYP, in which an equal distribution in the cytoplasm and the nucleus was more common (p = 0.9). Conclusions: The lower Gal-3 expression in MF-T in comparison to CD30 LPD might be an additional criterion to differentiate both entities. The different sublocalization of the Gal-3 signal might reflect a different biological function and behavior. © 2015 S. Karger AG, Basel.
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| 5. |
- Mitteldorf, C., et al.
(author)
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PD-1 and PD-L1 in neoplastic cells and the tumor microenvironment of Merkel cell carcinoma
- 2017
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In: Journal of cutaneous pathology. - : Blackwell Publishing Ltd. - 0303-6987 .- 1600-0560. ; 44:9, s. 740-746
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Journal article (peer-reviewed)abstract
- Background: Merkel cell carcinoma (MCC) is an aggressive neoplasm, which is often associated with Merkel cell polyomavirus (MCPyV). Programmed death-1 (PD-1) and its ligand PD-L1 are key players of the tumor microenvironment (TME). Methods: Fourteen paraffin-embedded tissue samples of MCC were stratified by their MCPyV detection. Apart from PD-L1 and PD-1, the TME was further characterized for the expression of CD33, FOXP3 and MxA. Results: We observed PD-1 in 2 of 12 tumors. PD-L1 expression by tumor cells was found in 7 of 8 MCPyV(+) samples and was detected particularly in the periphery. The tumor cells were surrounded by a shield of PD-L1/CD33 immune cells. Expression of PD-L1 by the tumor cells was higher in areas with a denser immune infiltrate. CD33(+) cells without direct tumor contact were PD-L1 negative. Only a low number of FOXP3(+) regulatory T-cells was admixed. Tumor cells of MCPyV(−) samples were mostly PD-L1 negative. Conclusions: Our data demonstrate that PD-L1 expression occurs in tumor and immune cells, in areas in which they are close in contact. Interferon seems to play a role in this interaction. We postulate that PD-L1(+)/CD33(+) cells shield the tumor against attacking PD-1(+) immune cells. Therefore, next to anti-PD-1/PD-L1 antibodies, blockade of CD33 seems to be a promising therapeutic approach. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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