Lymphoma

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 downregulates 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.

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Fig. 1: The cAMP/PDE4 axis modulate PD-L1 expression in DLBCL.
Fig. 2: Modulation of PD-L1 expression by the cAMP-PDE4 axis in vivo.
Fig. 3: Secreted factors acting on the JAK/STAT signals mediate cAMP induction of PD-L1 expression.
Fig. 4: Cyclic-AMP initiates a cytokine executed autocrine loop that promotes PD-L1 expression.
Fig. 5: Combination of PDE4 inhibition and checkpoint blockade in a syngeneic murine model of B-cell lymphoma.
Fig. 6: Graphic representation of the signaling axis linking cAMP to PD-L1 expression.

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Acknowledgements

RCTA was supported by RP150277, RP170146 (Cancer Prevention and Research Institute of Texas), TRP 6524-17(Leukemia and Lymphoma Society), R01ES031522 (NIEHS/NIH), and I01BX001882 (Veterans Administration Merit Award). The FACS core facility is supported by P30 CA054174 (NCI/NIH).

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BS designed, performed, and interpreted assays; PE, JM, and A-PL performed and interpreted experiments; SJ and ZQ provided support for in vivo assays; KNH, procured and characterized primary tumors; RCTA conceived the project, designed, and interpreted assays, wrote manuscript, which was reviewed and approved by all authors.

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Correspondence to Ricardo C. T. Aguiar.

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Sasi, B., Ethiraj, P., Myers, J. et al. Regulation of PD-L1 expression is a novel facet of cyclic-AMP-mediated immunosuppression. Leukemia (2020). https://doi.org/10.1038/s41375-020-01105-0

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