The role of complement-mediated signaling during antigen presentation

Abstract

Abstract Local production of complement C3a and C5a at the immune synapse by activated dendritic cells (DCs) enhances T cell responses in a variety of experimental systems. We have shown that complement C3 plays a mechanistic role in driving synergistic anti-tumor effects of blocking indoleamine 2,3-dioxygenase (IDO) during radiation and chemotherapy in a murine brain tumor model. We hypothesize that, when anti-tumor responses are allowed to happen, locally produced complement C3 acts as a costimulation factor for activation of T cells. To study the role of complement C3 in promoting T cell responses against a nominal tumor antigen (gp10025–33 peptide expressed by B16F10 melanoma), we used T cells from syngeneic pmel-1 mice (TCR transgenic with CD8 T cells that recognize the cross-presented gp10025–33 peptide). We found florid deposition of complement C3 in B16F10 tumors when IDO-blockade was added to a pmel-1/gp10025–33 based vaccine. To model homeostatic conditions of the tumor microenvironment, we used an in vitro co-culture system with gp10025–33 peptide in stringent limited supply. Under these conditions, pmel-1 CD8 T cells stimulated by DCs from complement C3 knock-out (C3-KO) mice had decreased activation marker expression, proliferation, and cytokine effector function, relative to pmel-1 CD8 T cells stimulated by DCs from wild-type (WT) mice. These findings suggest that suppression of local complement production by DCs in the tumor microenvironment may inhibit anti-tumor immune responses. Supported by grants from Alex's Lemonade Stand Foundation, Press On Foundation, and Hyundai Hope On Wheels.