Page 45 - Haematologica - Vol. 105 n. 6 - June 2020

CD20: functions and regulation
Idelalisib was also shown to decrease IFNγ production by NK cells, and reduce secretion of various cytokines by T cells (IL6, IL10, TNFα, and CD40L).115 More studies will be needed to determine whether other BTK or PI3K inhibitors have a better profile in terms of affecting ADCC/antibody-dependent cellular phagocytosis, but it seems inevitable that they will all lead to reduced levels of CD20.
The BH3-mimetic venetoclax was also tested in combi- nation with anti-CD20 monoclonal antibodies. It seems that in contrast to “BCR inhibitors”, there are no obvious biological reasons preventing an additive or synergistic effect of such a combination. The Food and Drug Administration granted approval for the use of venetoclax in combination with obinutuzumab for patients with pre- viously untreated CLL/small lymphocytic lymphoma and in combination with rituximab to treat patients with CLL/ small lymphocytic lymphoma who have received at least one prior therapy (Table 2).116 The biological ration- ale for such combinations in CLL is provided, among oth- ers, by a study showing that combining venetoclax and anti-CD20 monoclonal antibodies overcomes microenvi- ronment-mediated resistance of CLL cells to venetoclax monotherapy in vitro.117
Conclusion
Although CD20 is considered to be an ideal therapeutic target and rituximab-based immunotherapy has become a standard of care for a majority of B-cell malignancies, it is still unclear what all the functions of CD20 are, and
how its expression is regulated. The main reason is the large heterogeneity of patients with B-cell malignancies and the lack of mouse models with an evident phenotype which makes CD20 analysis in vivo more difficult. A full understanding of the complexity of regulation of CD20, its physiological function and the exact mechanism of action of anti-CD20 monoclonal antibodies is of pivotal importance to develop new modified anti-CD20 mono- clonal antibodies and their therapeutic combination that would yield better clinical efficacy and/or less toxicity. Recently, the possible role of CD20 in microenvironmen- tal interactions was underscored by the observation that CD20 is upregulated in the context of immune niches. This is likely to be of physiological importance, especially for BCR signaling; however, it is unclear if this is related to the putative function of CD20 as a regulator of calcium flux triggered by BCR or any potential role in T-cell inter- actions or some additional function(s). Further investiga- tion of the physiological function of CD20 is required, including the identification of molecules that interact with CD20, since this has implications for the develop- ment of rational therapeutic combinations and strategies.
Acknowledgments
Supported by the Ministry of Health of the Czech Republic, grant No. NU20-03-00292. All rights reserved. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innova- tion programme (grant agreement n. 802644). Figures were cre- ated using BioRender graphical tool. We would like to thank Prof. Jiri Mayer, MD (University Hospital Brno) for inspiring discussions about anti-CD20 monoclonal antibodies.
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