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Editorials
most other B-cell markers are downregulated by HRS cells.
In their study, Li and collagues studied several aspects of CD83 in HL (Figure 1).3 First, they validated that over 80% of cases of classical HL show CD83 expression by HRS cells, and they report that in the positive cases the fraction of CD83+ HRS cells varies from 10% to more than 90%. Second, they show that in vitro, CD83 can be transfered from HL cell line cells to T cells by trogocyto- sis. Trogocytosis is a process in which fragments of cell membranes are transfered from one cell to another.13 Interestingly, the trogocytosed CD4+ T cells that acquired CD83 though this process upregulated PD-1 expression, and consequently may become further suppressed in their activity against HRS cells. However, it remains unclear whether this is due to CD83 or other conse- quences of acquisition of membrane fragments from HRS cells. Third, extending upon an earlier observation by Hart and colleagues that a HL cell line releases sCD83,14 the group now shows that this is also a feature of other HL cell lines, and that sCD83 contributes to the inhibition of the proliferation of stimulated T cells. This became evi- dent from the observation that the inhibitory effect of supernatants from HL cell line cultures on T-cell prolifer- ation was partially abolished when sCD83 in the super- natants was captured by an anti-CD83 antibody. Fourth, serum levels of sCD83, measured by the enzyme-linked immunosorbent assay (ELISA), correlated with clinical response; this, however, requires more detailed analyses, as only six patients were studied in the work by Li and colleagues. Fifth, a human anti-human anti-CD83 anti- body (3C12C) was tested for its suitability to target HRS cells. Whereas the unconjugated antibody had variable cytotoxic effetcs when tested on three HL cell lines, toxi- city became more pronounced and consistent when the antibody was coupled to monomethyl auristatin E (MMAE). The unconjugated form showed no general tox- icity when applied to non-human primates, baboons. However, B-cell numbers where reduced in the animals, a fact from which the authors conclude that 3C12C has a targeted effect, as a fraction of B cells in baboons express- es CD83. Thus, 3C12C-MMAE should be further modi- fied and tested as a novel targeted treatment option for HL patients.
The multifaceted study by Derek Hart and his team addresses a multitude of aspects about the biology of CD83 in HL and its clinical implications. This will, hope- fully, stimulate more investigative work on this interest- ing topic. Regarding the application of the anti-CD83 antibody for the treatment of HL patients, a number of critical questions need to be addressed in future studies. The presence of sCD83 in HL patients may pose a major restriction for a successful therapy by capturing anti- CD83 antibodies, which may cause difficulty in obtaining high enough concentrations of free antibody in the lymph nodes to attack the HRS cells. It is a possibility that the capturing of sCD83 may be part of an efficient therapy, as
sCD83 has immunosuppressive features, therefore reduc- ing its concentration may work synergistically with the direct killing of HRS cells. A further caveat is that 3C12C- MMAE may also eliminate mature dendritic cells, which are CD83+, and thereby impair normal immune responses in patients. Neverheless, positive therapeutic effects may predominate also in this regard if dendritic cells in the HL microenvironment, which are considered to contribute to the complex immune evasion strategies in HL,2,15 are effi- ciently eliminated by the antibody-drug conjugate treat- ment. Moreover, although administration of 3C12C had no toxic effects on baboons, it remains to be clarified what the off-target toxicity of the toxin-coupled form of the antibody is, this being that which one would like to use in therapy. Finally, as most cases of HL express CD83 at levels detectable by immunohistochemistry only on a fraction of HRS cells (whereas CD30, the target of bren- tuximab vedotin, is expressed on virtually all HRS cells), it remains to be clarified how efficiently the HRS cell clone is eliminated when exposed to the anti-CD83 anti- body toxin conjugate.
References
1. Eichenauer DA, Engert A. The evolving role of targeted drugs in the treatment of Hodgkin lymphoma. Expert Rev Hematol. 2017;10(9):775-782.
2. Wein F, Küppers R. The role of T cells in the microenvironment of Hodgkin lymphoma. J Leukoc Biol. 2016;99(1):45-50.
3. Li Z, Ju X, Lee K, et al. CD83 is a new potential biomarker and therapeutic target for Hodgkin lymphoma. Haematologica. 2018;103(4):655-665.
4. Fujimoto Y, Tedder TF. CD83: a regulatory molecule of the immune system with great potential for therapeutic application. J Med Dent Sci. 2006;53(2):85-91.
5. Horvatinovich JM, Grogan EW, Norris M, et al. Soluble CD83 inhibits T cell activation by binding to the TLR4/MD-2 complex on CD14+ monocytes. J Immunol. 2017;198(6):2286-2301.
6. Breloer M, Fleischer B. CD83 regulates lymphocyte maturation, acti- vation and homeostasis. Trends Immunol. 2008;29(4):186-194.
7. Sorg UR, Morse TM, Patton WN, et al. Hodgkin's cells express CD83, a dendritic cell lineage associated antigen. Pathology. 1997;29(3):294-299.
8. Döring C, Hansmann ML, Agostinelli C, et al. A novel immunohis- tochemical classifier to distinguish Hodgkin lymphoma from ALK anaplastic large cell lymphoma. Mod Pathol. 2014;27(10):1345-1354.
9. Victora GD, Dominguez-Sola D, Holmes AB, Deroubaix S, Dalla- Favera R, Nussenzweig MC. Identification of human germinal center light and dark zone cells and their relationship to human B-cell lym- phomas. Blood. 2012;120(11):2240-2248.
10. Küppers R, Engert A, Hansmann M-L. Hodgkin lymphoma. J Clin Invest. 2012;122(10):3439-3447.
11. Schwering I, Bräuninger A, Klein U, et al. Loss of the B-lineage-spe- cific gene expression program in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma. Blood. 2003;101(4):1505-1512.
12. Tiacci E, Döring C, Brune V, et al. Analyzing primary Hodgkin and Reed-Sternberg cells to capture the molecular and cellular pathogen- esis of classical Hodgkin lymphoma. Blood. 2012;120(23):4609-4620.
13. DhainautM,MoserM.Regulationofimmunereactivitybyintercel- lular transfer. Front Immunol. 2014;5:112.
14. Hock BD, Kato M, McKenzie JL, Hart DN. A soluble form of CD83 is released from activated dendritic cells and B lymphocytes, and is detectable in normal human sera. Int Immunol. 2001;13(7):959-967.
15. Wein F, Weniger MA, Hoing B, et al. Complex immune evasion strategies in classical Hodgkin lymphoma. Cancer Immunol Res. 2017;5(12):1122-1132.
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