Regulation of PD-L1 expression is a novel facet of cyclic-AMP-mediated immunosuppression

Abstract

Cyclic-AMP (cAMP) exerts suppressive effects in the innate and adaptive immune system. The PD-1/PD-L1 immune checkpoint down-regulates T-cell activity. Here, we examined if these two immunosuppressive nodes intersect. Using normal and malignant lymphocytes from humans, and the phosphodiesterase 4b (Pde4b) knockout mouse, we found that cAMP induces PD-L1 transcription and protein expression. Mechanistically, we discovered that the cAMP effectors PKA and CREB induce the transcription/secretion of IL-10, IL-8 and IL-6, which initiate an autocrine loop that activates the JAK/STAT pathway and ultimately increase PD-L1 expression in the cell surface. This signaling axis is disarmed at two specific nodes in subsets of diffuse large B cell lymphoma, which may help explain the variable PD-L1 expression in these tumors. In vivo, we found that despite its immunosuppressive attributes, the PDE4 inhibitor roflumilast did not decrease the clinical activity of checkpoint inhibitors, an important clinical observation given the approved use of these agents in multiple diseases. In summary, we discovered that PD-L1 induction is a part of the repertoire of immunosuppressive actions mediated by cAMP, defined a cytokine-mediated autocrine loop that executes this action and, reassuringly, showed that PDE4 inhibition does not antagonize immune checkpoint blockade in an in vivo syngeneic lymphoma model.

CD73 Promotes Chronic Lymphocytic Leukemia

“…Our observation of female-specific increases in CD39 expression on B cells may reflect a sex-specific accumulation of IL-10-secreting Bregs, as was documented in humans [29]. While the impact of adenosine signaling on IL-10 production during CLL remains unknown, cAMP accumulation was recently described to favor IL-10 production in DLBCL [24]. IL-10 notably plays a critical role in CLL pathogenesis [30,31] and in the regulation of PD-L1 expression [24,25].…”

“…The A2a adenosine receptor is highly expressed on CLL cells [10]. Notably, cAMP signaling has been shown to enhance PD-L1 expression on diffuse large B cells' leukemia (DLBCL) cells [24]. Our data thus suggest that A2a receptor-mediated cAMP accumulation also promotes PD-L1 expression on CLL cells.…”

“…While the impact of adenosine signaling on IL-10 production during CLL remains unknown, cAMP accumulation was recently described to favor IL-10 production in DLBCL [24]. IL-10 notably plays a critical role in CLL pathogenesis [30,31] and in the regulation of PD-L1 expression [24,25]. Sex-mediated differences in IL-10 production, as described in solid tumors [32], may thus contribute to the sex bias of CD73-deficient Eµ-TCL1 tg/wt mice.…”

“…We investigated whether adenosine signaling regulated PD-L1 expression on leukemic cells. CLL cells were treated with NECA, a stable adenosine receptor agonist, with or without exogenous IL-10 and IFN-γ, which have been shown to modulate PD-L1 expression on CLL [24,25]. Remarkably, treatment with NECA significantly increased PD-L1 expression on CLL cells, an effect further exacerbated when cells were co-treated with IL-10 or IFN-γ (Figure 5A,B).…”

Immune checkpoint skewing might be the cause of continuous immune activation in nasal polyps: New opportunities for therapies

“…Immune checkpoint expression could be induced by cytokines, including IFN-g, TNF-a, and IL-6, resulting in upregulation of PD-L1 in a Janus kinase/signal transducer and activator of transcription (JAK/STAT)-dependent manner and attenuation of the activation of immune cells. 6 Recently published papers have described the underlying mechanism of immune checkpoints via the activation of adenylyl cyclase as a result of immunosuppressive mediators such as prostaglandin E 2 (PGE2). Adenylyl cyclases are found on all cells and are linked to G-protein-coupled receptors; they cause the formation of cyclic AMP (cAMP).…”