Interrogating the CD47-SIRP axis in chronic T cell stimulation to translate novel Graft-versus-host disease therapies 2473

Abstract Description Graft-versus-Host disease (GvHD) is a major complication associated with hematopoietic stem cell transplants (HSCTs), characterized by alloreactive immunotoxicity of the graft towards the immunocompromised patient. GvHD affects 40-50% of HSCT patients with an average 3-year survival of just 43%, underlining the need for novel therapies. CD47 the ‘don’t-eat-me’ signal, ligates with Signal Regulatory Protein alpha (SIRPa), an inhibitory transmembrane receptor on myeloid cells, preventing target cell phagocytosis. In cancer therapy, CD47-blockers are investigated as novel immunotherapies to promote cancer cell phagocytosis. Serendipitously, we found that either CD47 or pan-SIRP blockade effectively alleviated GvHD in a murine xeno-GvHD model. Phagocytosis was found not to be the main driver of GvHD alleviation, leading us to investigate SIRP proteins as potential regulators of chronic T cell stimulation. Particularly SIRP gamma (SIRPg), an understudied family member with unknown function, signaling, regulators and downstream effectors is exclusively expressed on T cells, and is known to be the only other SIRP to ligate CD47. In this work we could show that SIRPg expression is upregulated during chronic T cell stimulation and that its expression levels correlate with exhaustion and T cell differentiation marker expression in clinical scRNA seq data sets. Primary human SIRPg KO T cells show reduced pro-inflammatory cytokine secretion and a delayed onset of xeno-GvHD in vivo. Funding Sources Supported by R35 CA241894/CA/NCI NIH HHS/United States Topic Categories Transplantation Immunology (TRAN)