PD-1 Blockade and CD27 Stimulation Activate Distinct Transcriptional Programs That Synergize for CD8+ T-Cell–Driven Antitumor Immunity

Abstract

PD-1 checkpoint blockade has revolutionized the field of cancer immunotherapy, yet the frequency of responding patients is limited by inadequate T-cell priming secondary to a paucity of activatory dendritic cells (DC). DC signals can be bypassed by CD27 agonists, and we therefore investigated if the effectiveness of anti-PD-1/L1 could be improved by combining with agonist anti-CD27 monoclonal antibodies (mAb). The efficacy of PD-1/L1 blockade or agonist anti-CD27 mAb was compared with a dual-therapy approach in multiple tumor models. Global transcriptional profiling and flow cytometry analysis were used to delineate mechanisms underpinning the observed synergy. PD-1/PD-L1 blockade and agonist anti-CD27 mAb synergize for increased CD8 T-cell expansion and effector function, exemplified by enhanced IFNγ, TNFα, granzyme B, and T-bet. Transcriptome analysis of CD8 T cells revealed that combination therapy triggered a convergent program largely driven by IL2 and Myc. However, division of labor was also apparent such that anti-PD-1/L1 activates a cytotoxicity-gene expression program whereas anti-CD27 preferentially augments proliferation. In tumor models, either dependent on endogenous CD8 T cells or adoptive transfer of transgenic T cells, anti-CD27 mAb synergized with PD-1/L1 blockade for antitumor immunity. Finally, we show that a clinically relevant anti-human CD27 mAb, varlilumab, similarly synergizes with PD-L1 blockade for protection against lymphoma in human-CD27 transgenic mice. Our findings suggest that suboptimal T-cell invigoration in cancer patients undergoing treatment with PD-1 checkpoint blockers will be improved by dual PD-1 blockade and CD27 agonism and provide mechanistic insight into how these approaches cooperate for CD8 T-cell activation. .

CD27 stimulation unveils the efficacy of linked class I/II peptide vaccines in poorly immunogenic tumors by orchestrating a coordinated CD4/CD8 T cell response

“…Recent studies have demonstrated that CD27 engagement can lead to Fas expression and T cell apoptosis, while other studies have seen an increased in the expression of the immune checkpoint PD-1. 42,43 In support of these observations, our supplemental Figure 4 demonstrates that administration of αhCD27 with vaccination increases the expression of PD-1 on CD8 + T cells. Importantly, a recent study showed that PD-1 blockade can augment the efficacy of αhCD27 administration in the absence of vaccination through increasing T cell cytotoxicity.…”

“…46,47 However, recent studies in both the pre-clinical and clinical settings have demonstrated that αhCD27 administration does not potentiate Treg function but instead results in Treg depletion and a lack of suppressive function. 37,42 Therefore, we believe an increase in Treg suppression is unlikely to be impairing efficacy in our model. Finally, tumors can still overcome potent immune responses through tumor editing, a scenario in which antigen-loss variants arise as a result of antigen-specific immune pressure.…”

Differential immune profiles distinguish the mutational subtypes of gastrointestinal stromal tumor

“…CD27 was found to be an important feature predictive of high PD-1 expression in our random forest model, which correctly identified high PD-1 expression in 93% of our testing GIST cohort. Agonistic CD27 antibodies already exist and have shown efficacy with anti-PD-1 in other models, suggesting that this may be an effective strategy for GIST (49). Similarly, the costimulatory and checkpoint receptors CD40 and BTLA, along with the immune checkpoint ligand PDCD1LG2 and the MHC class I protein MICB were features predictive of high PD-1 expression.…”

Antibodies to Costimulatory Receptor 4-1BB Enhance Anti-tumor Immunity via T Regulatory Cell Depletion and Promotion of CD8 T Cell Effector Function

“…In house (Williams et al, 2013) N/A Mouse: B16/BL6 In house (Buchan et. al., 2018) N/A Mouse: FVAX In house (Buchan et. al., 2018…”