Peptide/MHC tetramer-based sorting of CD8 T cells to a Leukemia antigen yields clonotypes drawn nonspecifically from an underlying restricted repertoire

Sally A. Hunsucker, Colleen S. McGary, Benjamin G. Vincent, Atim A. Enyenihi, Jennifer P. Waugh, Karen P. McKinnon, Lisa M. Bixby, Patricia A. Ropp, James M. Coghill, William A. Wood, Don A. Gabriel, Stefanie Sarantopoulos, Thomas C. Shea, Jonathan S. Serody, Gheath Alatrash, Tania Rodriguez-Cruz, Gregory Lizee, Adam S. Buntzman, Jeffrey A. Frelinger, Gary L. GlishPaul M. Armistead

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Testing of T cell-based cancer therapeutics often involves measuring cancer antigen-specific T-cell populations with the assumption that they arise from in vivo clonal expansion. This analysis, using peptide/MHC tetramers, is often ambiguous. From a leukemia cell line, we identified a CDK4-derived peptide epitope, UNC-CDK4-1 (ALTPVVVTL), that bound HLA-A02:01 with high affinity and could induce CD8+ T-cell responses in vitro. We identified UNCCDK4-1/HLA-A02:01 tetramer+ populations in 3 of 6 patients with acute myeloid leukemia who had undergone allogeneic stem cell transplantation. Using tetramer-based, single-cell sorting and T-cell receptor b (TCRb) sequencing, we identified recurrent UNC-CDK4-1 tetramer-associated TCRb clonotypes in a patient with aUNC-CDK4-1 tetramer+ population, suggestingin vivo T-cell expansion to UNC-CDK4-1. In parallel, we measured the patient's TCRb repertoire and found it to be highly restricted/oligoclonal. The UNC-CDK4-1 tetramer-associated TCRb clonotypes represented >17% of the entire TCRb repertoire - far in excess of the UNCCDK4-1 tetramer+ frequency - indicating that the recurrent TCRb clonotypes identified from UNC-CDK-4-1 tetramer+ cells were likely a consequence of the extremely constrained T-cell repertoire in the patient and not in vivo UNC-CDK4-1-driven clonal T-cell expansion. Mapping recurrent TCRb clonotype sequences onto TCRb repertoires can help confirm or refute antigen-specific T-cell expansion.

Original languageEnglish (US)
Pages (from-to)228-235
Number of pages8
JournalCancer Immunology Research
Volume3
Issue number3
DOIs
StatePublished - Mar 2015

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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    Hunsucker, S. A., McGary, C. S., Vincent, B. G., Enyenihi, A. A., Waugh, J. P., McKinnon, K. P., Bixby, L. M., Ropp, P. A., Coghill, J. M., Wood, W. A., Gabriel, D. A., Sarantopoulos, S., Shea, T. C., Serody, J. S., Alatrash, G., Rodriguez-Cruz, T., Lizee, G., Buntzman, A. S., Frelinger, J. A., ... Armistead, P. M. (2015). Peptide/MHC tetramer-based sorting of CD8 T cells to a Leukemia antigen yields clonotypes drawn nonspecifically from an underlying restricted repertoire. Cancer Immunology Research, 3(3), 228-235. https://doi.org/10.1158/2326-6066.CIR-14-0001