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Understanding CD8 + T-cell responses toward the native and alternate HLA-A*02:01-restricted WT1 epitope.

Authors :
Nguyen TH
Tan AC
Xiang SD
Goubier A
Harland KL
Clemens EB
Plebanski M
Kedzierska K
Source :
Clinical & translational immunology [Clin Transl Immunology] 2017 Mar 17; Vol. 6 (3), pp. e134. Date of Electronic Publication: 2017 Mar 17 (Print Publication: 2017).
Publication Year :
2017

Abstract

The Wilms' tumor 1 (WT1) antigen is expressed in solid and hematological malignancies, but not healthy tissues, making it a promising target for cancer immunotherapies. Immunodominant WT1 epitopes, the native HLA-A2/WT1 <subscript>126-134</subscript> ( R MFPNAPYL) (HLA-A2/RMFPNAPYL epitope (WT1A)) and its modified variant Y MFPNAPYL (HLA-A2/YMFPNAPYL epitope (WT1B)), can induce WT1-specific CD8 <superscript>+</superscript> T cells, although WT1B is more stably bound to HLA-A*02:01. Here, to further determine the benefits of those two targets, we assessed the naive precursor frequencies; immunogenicity and cross-reactivity of CD8 <superscript>+</superscript> T cells directed toward these two WT1 epitopes. Ex vivo naive WT1A- and WT1B-specific CD8 <superscript>+</superscript> T cells were detected in healthy HLA-A*02:01 <superscript>+</superscript> individuals with comparable precursor frequencies (1 in 10 <superscript>5</superscript> -10 <superscript>6</superscript> ) to other naive CD8 <superscript>+</superscript> T-cell pools (for example, A2/HIV-Gag <subscript>77-85</subscript> ), but as expected, ~100 × lower than those found in memory populations (influenza, A2/M1 <subscript>58-66</subscript> ; EBV, A2/BMLF1 <subscript>280-288</subscript> ). Importantly, only WT1A-specific naive precursors were detected in HLA-A2.1 mice. To further assess the immunogenicity and recruitment of CD8 <superscript>+</superscript> T cells responding to WT1A and WT1B, we immunized HLA-A2.1 mice with either peptide. WT1A immunization elicited numerically higher CD8 <superscript>+</superscript> T-cell responses to the native tumor epitope following re-stimulation, although both regimens produced functionally similar responses toward WT1A via cytokine analysis and CD107a expression. Interestingly, however, WT1B immunization generated cross-reactive CD8 <superscript>+</superscript> T-cell responses to WT1A and could be further expanded by WT1A peptide revealing two distinct populations of single- and cross-reactive WT1A <superscript>+</superscript> CD8 <superscript>+</superscript> T cells with unique T-cell receptor-αβ gene signatures. Therefore, although both epitopes are immunogenic, the clinical benefits of WT1B vaccination remains debatable and perhaps both peptides may have separate clinical benefits as treatment targets.<br />Competing Interests: The authors declare no conflict of interest.

Details

Language :
English
ISSN :
2050-0068
Volume :
6
Issue :
3
Database :
MEDLINE
Journal :
Clinical & translational immunology
Publication Type :
Academic Journal
Accession number :
28435676
Full Text :
https://doi.org/10.1038/cti.2017.4