Abstract
BackgroundMelanoma patients vaccinated with tumor-associated antigens frequently develop measurable peptide-specific CD8+ T cell responses; however, such responses often do not confer clinical benefit. Understanding why vaccine-elicited responses are beneficial in some patients but not in others will be important to improve targeted cancer immunotherapies.Methods and FindingsWe analyzed peptide-specific CD8+ T cell responses in detail, by generating and characterizing over 200 cytotoxic T lymphocyte clones derived from T cell responses to heteroclitic peptide vaccination, and compared these responses to endogenous anti-tumor T cell responses elicited naturally (a heteroclitic peptide is a modification of a native peptide sequence involving substitution of an amino acid at an anchor residue to enhance the immunogenicity of the peptide). We found that vaccine-elicited T cells are diverse in T cell receptor variable chain beta expression and exhibit a different recognition profile for heteroclitic versus native peptide. In particular, vaccine-elicited T cells respond to native peptide with predominantly low recognition efficiency—a measure of the sensitivity of a T cell to different cognate peptide concentrations for stimulation—and, as a result, are inefficient in tumor lysis. In contrast, endogenous tumor-associated-antigen-specific T cells show a predominantly high recognition efficiency for native peptide and efficiently lyse tumor targets.ConclusionsThese results suggest that factors that shape the peptide-specific T cell repertoire after vaccination may be different from those that affect the endogenous response. Furthermore, our findings suggest that current heteroclitic peptide vaccination protocols drive expansion of peptide-specific T cells with a diverse range of recognition efficiencies, a significant proportion of which are unable to respond to melanoma cells. Therefore, it is critical that the recognition efficiency of vaccine-elicited T cells be measured, with the goal of advancing those modalities that elicit T cells with the greatest potential of tumor reactivity.
Highlights
The immunotherapy of cancer holds promise in harnessing the host immune response to target tumor cells without harming normal tissues
Endogenous tumor-associated-antigen-specific T cells show a predominantly high recognition efficiency for native peptide and efficiently lyse tumor targets. These results suggest that factors that shape the peptide-specific T cell repertoire after vaccination may be different from those that affect the endogenous response
Our findings suggest that current heteroclitic peptide vaccination protocols drive expansion of peptide-specific T cells with a diverse range of recognition efficiencies, a significant proportion of which are unable to respond to melanoma cells
Summary
The immunotherapy of cancer holds promise in harnessing the host immune response to target tumor cells without harming normal tissues. The anti-tumor potential of TAA-specific CD8þ T cells has been illustrated by the demonstrated capacity of adoptive T cell therapy to reduce tumor size [1]. While endogenous anti-tumor CD8þ T cell responses may already exist in some cancer patients [2], vaccination with TAA-derived peptides, and in particular heteroclitic peptide analogs, increases the frequency of TAA-specific T cell responses to detectable levels in many patients [3,4,5,6,7,8,9]. Melanoma patients vaccinated with tumor-associated antigens frequently develop measurable peptide-specific CD8þ T cell responses; such responses often do not confer clinical benefit. Understanding why vaccine-elicited responses are beneficial in some patients but not in others will be important to improve targeted cancer immunotherapies
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