Overcoming constraints on T cells in the HBV-infected liver (360G-Wellcome-101849_Z_13_A)

My request for enhancement funding arises from the component of my existing award focused on developing T cell immunotherapy of hepatitis B and hepatocellular carcinoma using patient samples. We recently made important contributions to the testing of genetically redirected T cells for a first-in-man treatment of HBV-related hepatocellular carcinoma1. We are also collaborating with academic and pharmaceutical partners to develop immunotherapeutic vaccines aiming to boost antiviral T cells for hepatitis B control. However, these approaches remain limited by the profound exhaustion and other immune constraints imposed on T cells by high-level antigenic stimulation in the tolerogenic liver. Front-line candidates to revive T cells are checkpoint inhibitors such as PD-1 blockade. However, we have found that genetic knockdown of PD-1 can initiate detrimental effects in virus-specific T cells (Fig.1). The emerging concept that PD- 1 may actually be required to support long-term maintenance of T cells in the setting of persistent antigenic stimulation is underscored by recent work in murine models2, 3 and by our finding that liver-resident PD-1+T cells can remain highly functional (Pallett, in preparation). These discoveries underscore the need to investigate more fundamental drivers and mediators of T cell failure as alternatives or additions to checkpoint inhibition.