OX40- and CD27-Mediated Costimulation Synergizes with Anti–PD-L1 Blockade by Forcing Exhausted CD8+ T Cells To Exit Quiescence

Abstract

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.

Association of PD-1/PD-L axis expression with cytolytic activity, mutational load, and prognosis in melanoma and other solid tumors

“…Combining agents that target LAG-3, IDO, ICOS, TIM-3, 4-1BB, OX40, and CD27 with anti-PD-1/PD-L has been supported by preclinical models (53)(54)(55)(56)(57)(58)(59)(60), and many of these elements (e.g., LAG-3, TIM-3, IDO, and so forth) are currently being tested in clinical trials (https://clinicaltrials. gov; NCT01968109, NCT02608268, NCT02559492).…”

Treatment Regimen, Surgical Outcome, and T-cell Differentiation Influence Prognostic Benefit of Tumor-Infiltrating Lymphocytes in High-Grade Serous Ovarian Cancer

“…The 1F5 antibody is currently in phase I trial for the treatment of hematologic malignancies and solid tumors. Based on the coexpression of CD27 and PD1 on TIL, combining agonistic CD27 antibody with a checkpoint blockade targeting the PD1/PD-L1 axis might be of further interest, because preclinical studies have shown a synergistic effect of combinatorial antibody treatment (28). Currently, also other treatment strategies for HGSC are being explored including strategies targeting angiogenesis (e.g., bevacizumab) and PARP inhibitors in tumors with alterations in the homologous recombination repair pathway.…”

Expression of inhibitory receptors on intratumoral T cells modulates the activity of a T cell-bispecific antibody targeting folate receptor

“…These findings are in line with data from chronic viral infections where PD-1 blockade could only rescue T-cell subsets with intermediate but not high levels of PD-1 expression. 37 Approaches combining blockade of the PD-1/PD-L1 axis with agonistic antibodies to either OX40 or CD27 have been shown to temporarily restore functionality to exhausted T-cells in a murine bone marrow transplantation model 48 thereby leading to the loss of Tbet hi PD-1 int T-cells and contraction of the effector pool capable to sustain the immune response. Similarly, administration of low-dose IL-2 combined with PD-L1 blockade has been demonstrated to decrease inhibitory receptor expression and viral load in a chronic murine LCMV model as IL-2 treatment may foster the generation of a pool of CD44 hi PD-1 int T-cells that are more responsive to PD-L1 blockade.…”