These data demonstrate the potential for allogeneic immunotherapy with donor lymphocytes both to reduce relapse risk and to induce durable antitumor responses in patients with Hodgkin's lymphoma after hematopoietic stem-cell transplantation that incorporates in vivo T-cell depletion.

Exhaustion of chronically stimulated CD8+ T cells is a significant obstacle to immune control of chronic infections or tumors. Although co-inhibitory checkpoint blockade with anti-programmed death-ligand 1 (PD-L1) antibody can restore functions to exhausted T cell populations, recovery is often incomplete and dependent upon the pool size of a quiescent T-bethigh subset that express lower levels of PD-1. In a model where unhelped, HY-specific CD8+ T cells gradually lose function following transfer to male BMT recipients, we have explored the effect of shifting the balance away from co-inhibition and toward co-stimulation by combining anti-PD-L1 with agonistic antibodies to the tumor-necrosis factor receptor superfamily members, OX40 and CD27. Several weeks following T cell transfer, both agonistic antibodies but especially anti-CD27 demonstrated synergy with anti-PD-L1 by enhancing CD8+ T cell proliferation and effector cytokine generation. Anti-CD27 and anti-PD-L1 synergised by downregulating the expression of multiple quiescence-related genes concomitant with a reduced frequency of T-bethigh cells within the exhausted population. However, in the presence of persistent antigen, the CD8+ T cell response was not sustained and the overall size of the effector cytokine-producing pool eventually contracted to levels below that of controls. Thus, CD27-mediated co-stimulation can synergize with co-inhibitory checkpoint blockade to switch off molecular programs for quiescence in exhausted T cell populations but at the expense of losing precursor cells required to maintain a response.