A Cancer Vaccine Induces Expansion of NY-ESO-1-Specific Regulatory T Cells in Patients with Advanced Melanoma

Abstract

Cancer vaccines are designed to expand tumor antigen-specific T cells with effector function. However, they may also inadvertently expand regulatory T cells (Treg), which could seriously hamper clinical efficacy. To address this possibility, we developed a novel assay to detect antigen-specific Treg based on down-regulation of surface CD3 following TCR engagement, and used this approach to screen for Treg specific to the NY-ESO-1 tumor antigen in melanoma patients treated with the NY-ESO-1/ISCOMATRIXTM cancer vaccine. All patients tested had Treg (CD25bright FoxP3+ CD127neg) specific for at least one NY-ESO-1 epitope in the blood. Strikingly, comparison with pre-treatment samples revealed that many of these responses were induced or boosted by vaccination. The most frequently detected response was toward the HLA-DP4-restricted NY-ESO-1157–170 epitope, which is also recognized by effector T cells. Notably, functional Treg specific for an HLA-DR-restricted epitope within the NY-ESO-1115–132 peptide were also identified at high frequency in tumor tissue, suggesting that NY-ESO-1-specific Treg may suppress local anti-tumor immune responses. Together, our data provide compelling evidence for the ability of a cancer vaccine to expand tumor antigen-specific Treg in the setting of advanced cancer, a finding which should be given serious consideration in the design of future cancer vaccine clinical trials.

Adjuvants That Improve the Ratio of Antigen-Specific Effector to Regulatory T Cells Enhance Tumor Immunity

“…Immunotherapies that enhance antigenspecific Treg expansion and suppressive function delayed multi-cytokine-producing Teff activation, resulting in disease control (41,42). To date, the relationship between antigenspecific Teffs and Tregs has not been examined in detail in cancer, although some in vitro and observational reports exist [19][20][21]. Our study extends the knowledge base gained from previous investigations by comparing a large panel of adjuvants for their ability to modulate the vaccine-specific Teff: Treg balance.…”

“…These Tregs were shown to suppress proliferation of Teffs in an antigen-specific manner when cultured with tumor peptide-loaded dendritic cells (19). In a clinical study of patients with melanoma immunized with NY-ESO-1 protein in ISCOMATRIX, vaccination increased the frequency of NY-ESO-1-specific Tregs in peripheral blood mononuclear cells (PBMC) and tumor tissue (20). We have shown that therapeutic vaccination of patients with melanoma with Melan-A peptide plus CpG-ODN in Montanide results in robust expansion of Melan-A-specific CD8 þ T cells within PBMCs with a concomitant decrease in Melan-A-specific Tregs (1,2,21).…”

CD4+ T Effectors Specific for the Tumor Antigen NY-ESO-1 Are Highly Enriched at Ovarian Cancer Sites and Coexist with, but Are Distinct from, Tumor-Associated Treg

“…In our (18,19). These studies, however, did not use ex vivo assessments by tetramers, but indirect strategies that may have confounded results and conclusions.…”

A Potential Role for Immunotherapy in Thyroid Cancer by Enhancing NY-ESO-1 Cancer Antigen Expression

“…Strategies employing the treatment of cancer cells with demethylating agents as well as histone demethylase inhibitors to reactivate or increase the expression of the CTA genes including NY-ESO-1 have previously been published in glioma, myeloid leukemia, and melanoma (17)(18)(19)(20). Clinical trials are now underway using NY-ESO-1 targeted immunotherapeutic strategies that include use of genetically engineered T-cells transduced with NY-ESO-1-T-cell receptors (TCRs) directly targeting melanoma cells (21)(22)(23).…”