ABSTRACT
Antibodies that block T-cell-regulatory checkpoints have recently emerged as a transformative approach to cancer treatment. However, the clinical efficacy of checkpoint blockade depends upon inherent tumor immunogenicity, with variation in infiltrating T cells contributing to differences in objective response rates. Here, we sought to understand the molecular correlates of tumor-infiltrating T lymphocytes (TIL) in squamous cell carcinoma (SCC), using a systems biologic approach to integrate publicly available omics datasets with histopathologic features. We provide evidence that links TIL abundance and therapeutic outcome to the regulation of tumor glycolysis by EGFR and HIF, both of which are attractive molecular targets for use in combination with immunotherapeutics. Cancer Res; 76(14); 4136-48. ©2016 AACR.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Carcinoma, Squamous Cell/immunology , Glucose/metabolism , Head and Neck Neoplasms/immunology , Lymphocytes, Tumor-Infiltrating/immunology , Animals , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/mortality , ErbB Receptors/genetics , ErbB Receptors/physiology , Female , Glucose Transporter Type 1/analysis , Head and Neck Neoplasms/metabolism , Head and Neck Neoplasms/mortality , Hypoxia-Inducible Factor 1, alpha Subunit/physiology , Mice , Mice, Inbred C57BL , Squamous Cell Carcinoma of Head and Neck , Transcriptome , Up-RegulationABSTRACT
For long-term attack on tumor cells in patients with prostate cancer, induction of cytolytic T cells is desirable. Several lineage-specific target proteins are known and algorithms have identified candidate MHC class I-binding peptides, particularly for HLA-A*0201. We have designed tolerance-breaking DNA fusion vaccines incorporating a domain of tetanus toxin fused to candidate tumor-derived peptide sequences. Using three separate peptide sequences from prostate-specific membrane antigen (PSMA) (peptides PSMA(27) , PSMA(663) , and PSMA(711) ), this vaccine design induced high levels of CD8(+) T cells against each peptide in a HLA-A(*) 0201 preclinical model. In contrast, the full-length PSMA sequence containing all three epitopes was poorly immunogenic. Induced T cells were cytotoxic against peptide-loaded tumor cells, but only those against PSMA(27) or PSMA(663) peptides, and not PSMA(711) , were able to kill tumor cells expressing endogenous PSMA. Cytotoxicity was also evident in vivo. The preclinical model provides a powerful tool for generating CD8(+) T cells able to predict whether target cells can process and present peptides, essential for planning peptide vaccine-based clinical trials.
