TAP-independent self-peptides enhance T cell recognition of immune-escaped tumors
Elien M. Doorduijn, … , Sjoerd H. van der Burg, Thorbald van Hall
Elien M. Doorduijn, … , Sjoerd H. van der Burg, Thorbald van Hall
Published January 19, 2016
Citation Information: J Clin Invest. 2016;126(2):784-794. https://doi.org/10.1172/JCI83671.
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Research Article Immunology Oncology

TAP-independent self-peptides enhance T cell recognition of immune-escaped tumors

Abstract

Tumor cells frequently escape from CD8+ T cell recognition by abrogating MHC-I antigen presentation. Deficiency in processing components, like the transporter associated with antigen processing (TAP), results in strongly decreased surface display of peptide/MHC-I complexes. We previously identified a class of hidden self-antigens known as T cell epitopes associated with impaired peptide processing (TEIPP), which emerge on tumor cells with such processing defects. In the present study, we analyzed thymus selection and peripheral behavior of T cells with specificity for the prototypic TEIPP antigen, the “self” TRH4 peptide/Db complex. TEIPP T cells were efficiently selected in the thymus, egressed with a naive phenotype, and could be exploited for immunotherapy against immune-escaped, TAP-deficient tumor cells expressing low levels of MHC-I (MHC-Ilo). In contrast, overt thymus deletion and functionally impaired TEIPP T cells were observed in mice deficient for TAP1 due to TEIPP antigen presentation on all body cells in these mice. Our results strongly support the concept that TEIPPs derive from ubiquitous, nonmutated self-antigens and constitute a class of immunogenic neoantigens that are unmasked during tumor immune evasion. These data suggest that TEIPP-specific CD8+ T cells are promising candidates in the treatment of tumors that have escaped from conventional immunotherapies.

Authors

Elien M. Doorduijn, Marjolein Sluijter, Bianca J. Querido, Cláudia C. Oliveira, Adnane Achour, Ferry Ossendorp, Sjoerd H. van der Burg, Thorbald van Hall

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Figure 5

Peptide vaccination leads to cross-presented antigen and strong activation of TEIPP T cells.

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Peptide vaccination leads to cross-presented antigen and strong activati...
(A) DCs were loaded for 5 hours with purified 20-mer long TRH4 peptide. Cells were washed and cultured overnight with the LnB5 T cell clone. IFNγ was measured the following day by intracellular cytokine stain. Means and SD of triplicates from 1 of 3 experiments. Student t test, **P < 0.001. (B) Experimental setup. (C) Blood samples were analyzed by flow cytometry after cell transfer and vaccination. (D) IFNγ production by transferred LnB5 T cells, as measured by intracellular cytokine stain, was evaluated on blood samples on day 13 after T cell transfer. Shown are means with ± SEM from 1 of 3 experiments. (E and F) One week after the second vaccination, mice received peptide-loaded and CFSE-labeled splenocytes i.v. in a 1:1 ratio. Two days after challenge, spleens of recipient mice were analyzed for the presence of differentially labeled target cells. Data representative of 2 independent experiments with 3 mice per group. (G and H) Differentially CFSE-labeled C57BL/6 and Tap1–/– splenocytes were used as targets. Data represent means with ± SEM pooled from 2 independent experiments with 3 mice per group. One-way ANOVA, *P < 0.05, **P < 0.001.