PD-1 Is a Regulator of NY-ESO-1-Specific CD8+ T Cell Expansion in Melanoma Patients

Abstract

The programmed death 1 (PD-1) receptor is a negative regulator of activated T cells and is up-regulated on exhausted virus-specific CD8+ T cells in chronically infected mice and humans. Programmed death ligand 1 (PD-L1) is expressed by multiple tumors, and its interaction with PD-1 resulted in tumor escape in experimental models. To investigate the role of PD-1 in impairing spontaneous tumor Ag-specific CD8+ T cells in melanoma patients, we have examined the effect of PD-1 expression on ex vivo detectable CD8+ T cells specific to the tumor Ag NY-ESO-1. In contrast to EBV, influenza, or Melan-A/MART-1-specific CD8+ T cells, NY-ESO-1-specific CD8+ T cells up-regulated PD-1 expression. PD-1 up-regulation on spontaneous NY-ESO-1-specific CD8+ T cells occurs along with T cell activation and is not directly associated with an inability to produce cytokines. Importantly, blockade of the PD-1/PD-L1 pathway in combination with prolonged Ag stimulation with PD-L1+ APCs or melanoma cells augmented the number of cytokine-producing, proliferating, and total NY-ESO-1-specific CD8+ T cells. Collectively, our findings support the role of PD-1 as a regulator of NY-ESO-1-specific CD8+ T cell expansion in the context of chronic Ag stimulation. They further support the use of PD-1/PD-L1 pathway blockade in cancer patients to partially restore NY-ESO-1-specific CD8+ T cell numbers and functions, increasing the likelihood of tumor regression.

Tumor-infiltrating NY-ESO-1–specific CD8 + T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer

“…More recently, Fourcade et al reported that PD-1 expression was up-regulated on NY-ESO-1-specific CD8 + T cells in PBLs of melanoma patients, and PD-L1 pathway blockade enhanced the number of antigen-specific cytokine-producing CD8 + T cells (17). Here we have focused on coinhibitory pathway blockade ex vivo under different stimulating conditions and differentiation states of CD8 + T cells and observed distinct outcomes.…”

“…In previous studies, spontaneous NY-ESO-1-specific CD8 + T cell responses were detectable directly ex vivo in peripheral blood of melanoma patients who were seropositive for NY-ESO-1 (17). In a recent report by Milne et al on a single NY-ESO-1-seropositive EOC patient, corresponding ascites and solid tumor specimen were shown to be enriched (up to 6%) for NY-ESO-1-tetramer-reactive CD8 + T cells (18).…”

Strength of PD-1 signaling differentially affects T-cell effector functions

“…This approach allows us to probe exactly how PD-1 expression contributes to T-cell dysfunction without any other complicating factors. Most studies examining T-cell populations isolated from the peripheral blood of patients show that exhausted T cells have approximately three-to 10-fold more PD-1 than effector T cells (19,44,48). However, PD-1 expression on exhausted T cells can be modulated further by the severity of the infection, the size of the tumor (38), and the location of the T cell within the body (12,39).…”

“…Studying the effects of PD-1 blockade in restoring function to tumor-specific T cells also has resulted in inconsistent and conflicting data. In one study, interfering with PD-1/PD-L1 interactions resulted in augmented numbers of NY-ESO-1-specific T cells isolated from melanoma patients after 6 d of in vitro stimulation, and these T cells had a greater potential to produce effector cytokines than those expanded with PD-1 blockade (44,45). However, in vitro stimulation was required to observe the beneficial effects of PD-1 blockade, because no differences were noted when studying recently isolated PD-1 high NY-ESO-1-specific T cells, suggesting that the majority of tumor-specific T cells are unresponsive to PD-1 blockade.…”

Mechanism of T cell exhaustion in a chronic environment

“…A strong correlation between PD-1 ligand expression on tumor cells and unfavorable prognosis has been demonstrated for various cancers (38)(39)(40)(41)(42)(43)(44). Importantly, high expression of PD-1 on TILs has been reported (21,23,45), and PD-1 blockade has been shown to enhance the frequency of cytokine-producing cells (45). Currently, two humanized monoclonal antibodies against PD-1, ONO-4538/MDX-1106 and CT011, are in clinical trials for treatment of cancer and HCV infection.…”