Exposed phosphatidylserine is a non-classical inhibitory molecule during CD8 T cell exhaustion 2323

Abstract Description In cancer and chronic infection CD8 T cell exhaustion is hallmarked by inhibitory surface receptors such as PD-1, TIGIT, and CTLA-4. Thus, inhibitory receptor focus has been limited to surface proteins and an expansion into different classes of inhibitory molecules is needed. We identify the lipid metabolite phosphatidylserine (PS) as a regulator of T cell exhaustion. Live, exhausted, antigen specific CD8 T cells externalize high levels of PS in vivo in both cancer or LCMV infection. The exposed PS from exhausted T cells signaled extrinsically to suppress co-stimulatory molecule expression on dendritic cells. To evaluate if targeting exposed PS could stimulate the CD8 T cell response in exhaustion, we treated chronically infected mice with the anti-PS antibody mch1N11 and found that monotherapy alone expanded the PD-1+ antigen-specific CD8 T cell response. Most significantly, PD-1+ Tcf1+ stem-like CD8 T cells downregulated quiescence-associated gene modules and increased proliferation after aPS treatment. Combination of mch1N11 with aPD-L1 synergized to further increase the CD8 T cell effector response. In fact, the first clinical trial combining PS and PD-L1 antibodies was recently shown to have favorable anti-tumor responses. Therefore, our work details live PS CD8 T cell biology in vivo and provides novel a mechanism of action by which exposed PS facilitates suppressive T cell – DC interactions to function as a ‘non-classical’ inhibitory molecule during exhaustion. Funding Sources Hanna H. Gray Fellowship (GT16001) Burroughs Wellcome Fund – PDEP Fellowship (1022362) Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)