Programmed death-1 (PD-1) inhibitors aggravate the effector phase in a model of pemphigoid diseases by disinhibition of dermal γδ T cells

Summary: Abstract Body: Checkpoint inhibitors (CIs), particularly inhibitors of programmed death-1 (PD-1) and its ligand PD-L1, have become a mainstay of cancer therapy. The use of checkpoint inhibitors is supposedly associated with an increased risk for the development of bullous pemphigoid (BP). The mechanisms behind this putative side-effect are, however, still elusive. Thus, it is unknown, e.g., whether CIs may promote the break of tolerance or rather the precipitation of the effector phase. We therefore investigated the effect of ablating PD-1 signaling on skin inflammation in a mouse model of the effector phase of pemphigoid diseases, specifically the antibody transfer model of BP-like epidermolysis bullosa acquisita. Both inhibition of PD-1 by CIs and genetic deficiency of its gene Cd274 aggravated skin inflammation significantly. PD-1 inhibition increased the number of neutrophils in lesional skin, which is consistent with central role of this effector cell population in pemphigoid diseases. We profiled the cellular expression of PD-1 and PD-L1 in lesional skin by single-cell (sc)RNA sequencing and flow cytometric analysis and found PD-1 predominantly expressed on γδ T cells and NKT cells. PD-L1, in contrast, was widely expressed, including on neutrophils. Depleting of γδ T cells but not that of NKT cells nullified the aggravation of disease by PD-1 inhibition highlighting γδ T cells as crucial PD-1+ cell population. By gene expression analysis we found IL-17A expression significantly upregulated in γδ T cells upon PD-1 inhibition. IL-17A is known, among other, to amplify the recruitment of neutrophils into the skin and to extend the lifespan of neutrophils in inflamed tissues. Collectively, our results suggest that CIs may promote the effector of pemphigoid diseases by upregulating the expression of IL-17A in dermal γδ T cells. Jasper Prüßmann¹, Wiebke Prüßmann¹, Sripriya Murthy¹, Henning Olbrich¹, Jenny Tillmann¹, Jean-Paul Sayegh¹, Paul Schilf¹, Christian D. Sadik¹ 1. Department of Dermatology, Allergy, and Venereology, Universitat zu Lubeck, Lübeck, SH, Germany. Adaptive and Auto-Immunity