Peptide vaccines prevent tumor growth by activating T cells that respond to native tumor antigens

Abstract

Peptide vaccines enhance the response of T cells toward tumor antigens and represent a strategy to augment antigen-independent immunotherapies of cancer. However, peptide vaccines that include native tumor antigens rarely prevent tumor growth. We have assembled a set of peptide variants for a mouse-colon tumor model to determine how to improve T-cell responses. These peptides have similar affinity for MHC molecules, but differ in the affinity of the peptide-MHC/T-cell receptor interaction with a tumor-specific T-cell clone. We systematically demonstrated that effective antitumor responses are generated after vaccination with variant peptides that stimulate the largest proportion of endogenous T cells specific for the native tumor antigen. Importantly, we found some variant peptides that strongly stimulated a specific T-cell clone in vitro, but elicited fewer tumor-specific T cells in vivo, and were not protective. The T cells expanded by the effective vaccines responded to the wild-type antigen by making cytokines and killing target cells, whereas most of the T cells expanded by the ineffective vaccines only responded to the peptide variants. We conclude that peptide-variant vaccines are most effective when the peptides react with a large responsive part of the tumor-specific T-cell repertoire.

Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model

“…Soluble synthetic peptides were ≥ 95% pure (Chi Scientific) and stocks were diluted to 10 mg/ml in double distilled H 2 O. CD8+ T cells bearing TCRs specific for the immunodominant CT26 T cell epitope AH1 (15) were expanded in vivo through vaccination with peptide A5, as described (18). Mice were challenged subcutaneously with 5×10 4 CT26 tumor cells on the hind flank (21).…”

“…The majority of CT26 TIL express multiple inhibitory receptors and are hypofunctional (9). Nevertheless, mobilizing a functional CD8+ T cell response is necessary for successful anti-CT26 immunotherapy (18). …”

Translating Tumor Antigens into Cancer Vaccines

“…An alternative strategy is to generate peptide variants of TAAs (47,72,84), including mimotopes, heteroclitic peptides, altered-peptide ligands, and superagonists, introducing MHC-anchor residue modifications (127,181), systematic residue substitutions (161), combinatorial peptide libraries (111,139), and genetically encoded peptide libraries (39,191). However, considering the overall disappointing results of clinical trials testing such peptide variants, additional strategies have been developed to broaden the repertoire of responding T cells by introducing amino acid substitutions in the peptide-MHC binding surface (16,74,102).…”

Enhanced antitumor effects of a dendritic cell vaccine transfected with gastric cancer cell total RNA carrying the 4-1BBL gene in vitro

“…The activation of cytotoxic T lymphocyte (CTL) killing rate of tumor in the different DC groups (n=3, x±s). including a variety of tumor antigen encoded information; genetic material is easily available but not integrated into the host chromosome, so more secure; little damage to the DC is conductive to maintaining the activity and presenting function of the cell; RNA may be isolated from a small amount of tumor tissue and may be amplified to provide an adequate amount of material; comprehensive immune responses are induced to prevent antigenic variation and immune escape due to antigenic variation (8)(9)(10). The 4-1BB/4-1BBL receptor/ligand pair is another crucial co-stimulatory signal besides CD28/B7 in immune response and tumor immunity.…”