Abstract
SummaryChemotherapy pre-conditioning is an essential component of chimeric antigen receptor transduced cell therapy. Acute lymphopenia-induced proliferation (LIP) is known to be driven primarily by homeostatic cytokines, but little is known on the underlying mechanisms in humans. We undertook phenotypic and transcriptional analysis of T cells undergoing LIP two weeks post-myeloablative autograft stem cell transplantation. Strong IL-7 signaling was reflected in downregulated IL-7R expression on all T cells, including naive cells, along with parallel increased IL-2Rα expression. Notably, activated residual naive cells expressed Fas indicating recent TCR engagement. Moreover, proportion of Ki67 + FoxP3+ Tregs was almost doubled. Transcriptional analysis revealed increased fatty acid metabolism and interferon signaling responses. In contrast, TGF-β signaling was strongly suppressed. Thus, human LIP response is characterized by cytokine and TCR-driven proliferation which drives global T cell activation but also preferentially triggers regulatory cell expansion which may limit tumor-specific immunity. These features indicate potential therapeutic opportunities to manipulate immunotherapy regimens incorporating LIP conditioning protocols.
Highlights
A characteristic feature of the immune system is the maintenance of a stable lymphoid pool with relatively little fluctuation in lymphocyte number over time
SUMMARY Chemotherapy pre-conditioning is an essential component of chimeric antigen receptor transduced cell therapy
Acute lymphopenia-induced proliferation (LIP) is known to be driven primarily by homeostatic cytokines, but little is known on the underlying mechanisms in humans
Summary
A characteristic feature of the immune system is the maintenance of a stable lymphoid pool with relatively little fluctuation in lymphocyte number over time. Homeostatic proliferation is one mechanism by which this is achieved and refers to the ability of lymphoid cells to increase proliferation during periods of acute and chronic lymphopenia (Takada and Jameson, 2009) (Mackall and Gress, 1997). The homeostatic cytokines IL-7 and IL-15 are important mediators in this regard with IL-7 acting as a primary ‘rheostat’ through its proliferative and anti-apoptotic activity. IL-7 is produced by a range of stromal cells and serum concentrations are regulated through consumption by lymphoid populations (Martin et al, 2017). IL-7 concentrations increase during lymphopenia (Condomines et al, 2010) and act to drive increased lymphoproliferation (Perales et al, 2012). IL-15 mediates its effect primarily on memory CD8+ T cells and natural killer cells. Profound lymphopenia leads to lymphopenia-induced proliferation (LIP) and in this setting murine models indicate that T cell receptor engagement promotes proliferation through recognition of self-peptides by naive T cells (Winstead et al, 2010) (Goldrath et al, 2000) (Cho et al, 2016)
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