Abstract
Antibodies that block the interaction between programmed death ligand 1 (PD-L1) and PD-1 have shown impressive responses in subgroups of patients with cancer. PD-L1 expression in tumors seems to be a prerequisite for treatment response. However, PD-L1 is heterogeneously expressed within tumor lesions and may change upon disease progression and treatment. Imaging of PD-L1 could aid in patient selection. Previously, we showed the feasibility to image PD-L1+ tumors in immunodeficient mice. However, PD-L1 is also expressed on immune cell subsets. Therefore, the aim of this study was to assess the potential of PD-L1 micro single-photon emission tomography/computed tomography (microSPECT/CT) using radiolabeled PD-L1 antibodies to (i) measure PD-L1 expression in two immunocompetent tumor models (syngeneic mice and humanized mice harboring PD-L1 expressing immune cells) and (ii) monitor therapy-induced changes in tumor PD-L1 expression. We showed that radiolabeled PD-L1 antibodies accumulated preferentially in PD-L1+ tumors, despite considerable uptake in certain normal lymphoid tissues (spleen and lymph nodes) and nonlymphoid tissues (duodenum and brown fat). PD-L1 microSPECT/CT imaging could also distinguish between high and low PD-L1-expressing tumors. The presence of PD-L1+ immune cells did not compromise tumor uptake of the human PD-L1 antibodies in humanized mice, and we demonstrated that radiotherapy-induced upregulation of PD-L1 expression in murine tumors could be monitored with microSPECT/CT imaging. Together, these data demonstrate that PD-L1 microSPECT/CT is a sensitive technique to detect variations in tumor PD-L1 expression, and in the future, this technique may enable patient selection for PD-1/PD-L1-targeted therapy.
Highlights
In the past years, checkpoint blockade has shown impressive efficacy in the treatment of patients with cancer
We observed efficient binding of 111In–anti–mPD-L1 and 111In–anti–hPD-L1 to PD-L1þ Renca and MDA-MB-231 tumor cells, respectively (Fig. 1A). This was blocked by treatment with excess unlabeled anti–mPD-L1 or anti–hPD-L1, demonstrating the binding specificity of the radiolabeled antibodies for programmed death ligand 1 (PD-L1), and radiolabeled isotype control antibodies did not bind to these PD-L1þ tumors cells. 111In–anti–mPD-L1 showed the highest binding to Renca cells, followed by B16F1, 4T1, LLC1, and CT26 (Fig. 1B)
We observed that after a 24-hour incubation, 41% Æ 0.4% of the cellassociated activity was internalized, whereas the remaining 59% Æ 0.4% was still membrane bound (Fig. 1D). These data demonstrated that 111In–anti–mPD-L1 binds to PD-L1–expressing tumor cells
Summary
Checkpoint blockade has shown impressive efficacy in the treatment of patients with cancer. In this anticancer therapy, boosting of tumor-attacking T cells plays a critical role. Effective activation of tumor-reactive T cells requires (i) T-cell receptor recognition of the corresponding epitope presented by the major histocompatibility complex and (ii) signaling via costimulatory molecules, such as CD28, following interaction with their cognate ligands (i.e., CD80/86) expressed by the antigen-presenting cells. T-cell response is further regulated by coinhibitory signaling molecules, including programmed death-1 PD-1 is expressed by activated T cells and has two ligands, programmed death ligand-1 (PD-L1) and PD-L2. By upregulating PD-L1, tumors can escape immune recognition and attack [2,3,4]
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