Abstract
The PI3Kδ-inhibitor Idelalisib is approved for the treatment of Non-Hodgkin lymphoma. However, its use has been decreased within the last years due to deleterious infections such as cytomegalovirus and pneumocystis jirovecii. Here, we have investigated the effect of Idelalisib on human monocyte-derived dendritic cells (DCs) as important players in the induction of immune responses. We found that Idelalisib-treated DCs displayed impaired T cell stimulatory function. PI3Kδ inhibition during differentiation resulted in decreased Interleukin-12, Interleukin-13 and TNFα production by DCs after lipopolysaccharide stimulation. Moreover, DCs showed decreased expression of the activation marker CD83 after Idelalisib treatment. Further, in line with this was the failure of Idelalisib-treated DCs to properly induce allogeneic T cells in a dose-dependent manner. Finally, activation of the NFκB pathway was also ablated in Idelalisib-treated DCs. Our results implicate that severe infectious complications may not only result from direct PI3Kδ-inhibition in T cells, but also from impaired DC function in Idelalisib-treated patients. Here, we provide new insight into the pathogenesis of Idelalisib-associated infectious complications. Our study may further provide a rationale for the use of Idelalisib as a novel therapeutic option in inflammatory diseases.
Highlights
Non-Hodgkin lymphoma, like follicular lymphoma (FL) and small lymphocytic lymphoma/chronic lymphatic leukemia (SLL/CLL), are hematological malignancies characterized by uncontrolled proliferation of clonal B cells, which leads to painless lymphadenopathy in most cases
We investigated the effect of Idelalisib on Dendritic cells (DCs) function, which is a prerequisite for appropriate T cell activation, differentiation and proliferation
To understand dose-dependent effects of the PI3Kδ inhibitor on lineage and activation markers, we differentiated monocytes into moDCs in the presence of GM-CSF and IL-4
Summary
Non-Hodgkin lymphoma, like follicular lymphoma (FL) and small lymphocytic lymphoma/chronic lymphatic leukemia (SLL/CLL), are hematological malignancies characterized by uncontrolled proliferation of clonal B cells, which leads to painless lymphadenopathy in most cases. Any organ may be affected, which is reflected by the broad variety of clinical presentations of these diseases [1]. T cell-mediated immunity and the induction of a potent immune response are T cell-dependent, and require professional antigen-presenting cells (APCs). We investigated the effect of Idelalisib on DC function, which is a prerequisite for appropriate T cell activation, differentiation and proliferation. Our study may highlight how PI3Kδ inhibition diminishes T cell function directly, and affects antigen-specific T cell responses through attenuated DC function
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