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Abstract
PD-L1 (CD274) contributes to functional exhaustion of T cells and limits immune responses in patients with cancer. In this study, we report the identification of an human leukocyte antigen (HLA)-A2-restricted epitope from PD-L1, and we describe natural, cytolytic T-cell reactivity against PD-L1 in the peripheral blood of patients with cancer and healthy individuals. Notably, PD-L1-specific T cells were able not only to recognize and kill tumor cells but also PD-L1-expressing dendritic cells in a PD-L1-dependent manner, insofar as PD-L1 ablation rescued dendritic cells from killing. Furthermore, by incubating nonprofessional antigen-presenting cells with long peptides from PD-L1, we found that PD-L1 was rapidly internalized, processed, and cross-presented by HLA-A2 on the cell surface. Apparently, this cross-presentation was TAP-independent, as it was conducted not only by B cells but in addition by TAP-deficient T2-cells. This is intriguing, as soluble PD-L1 has been detected in the sera from patients with cancer. PD-L1-specific CTL may boost immunity by the killing of immunosuppressive tumor cells as well as regulatory cells. However, PD-L1-specific CTLs may as well suppress immunity by the elimination of normal immune cells especially PD-L1 expressing mature dendritic cells.
Highlights
Harnessing of the immune system to combat cancer has achieved major breakthroughs over the past few years
The presence of PD-L1–reactive T cells in the blood of patients with human leukocyte antigen (HLA)-A2þ cancer were revealed by IFN-g ELISPOT (Fig. 1B)
PD-L1–specific T cells could be found among Peripheral blood mononuclear cells (PBMC) healthy individuals, it seemed to be less frequent than in patients with cancer, a Mann–Whitney test illustrated that this difference not reached significance (P 1⁄4 0.06)
Summary
Harnessing of the immune system to combat cancer has achieved major breakthroughs over the past few years. Despite the fact that malignant transformation is associated with the expression of immunogenic antigens, the immune system often fails to respond effectively and becomes tolerant toward these antigens [1]. It is recognized that it is essential to overcome this acquired state of tolerance for cancer immunotherapy to succeed. In this regard, the anti-CTLA-4 blocking antibody ipilimumab (Yervoy, Bristol-Myers Squibb) was recently approved by the U.S Food and Drug Administration (FDA) for the treatment of melanoma after showing effect in clinical phase III studies. CTLA-4 is a key inhibitory receptor that critically affects peripheral T-cell tolerance and T-cell function [2].
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