Tumor- and neoantigen-reactive T-cell receptors can be identified based on their frequency in fresh tumor

Anna Pasetto, Alena Gros, Paul F. Robbins, Drew C. Deniger, Todd D. Prickett, Rodrigo Matus-Nicodemos, Daniel C. Douek, Bryan Howie, Harlan Robins, Maria R. Parkhurst, Jared Gartner, Katarzyna Trebska-McGowan, Jessica S. Crystal, Steven A. Rosenberg

Research output: Contribution to journalArticle

Abstract

AdoptivetransferofTcellswithengineeredT-cellreceptor(TCR) genes that target tumor-specific antigens can mediate cancer regression.Accumulatingevidencesuggeststhattheclinicalsuccess ofmanyimmunotherapiesismediatedbyTcellstargetingmutated neoantigens unique to the patient. We hypothesized that the most frequent TCR clonotypes infiltrating the tumor were reactive against tumor antigens. To test this hypothesis, we developed a multistep strategy that involved TCRB deep sequencing of the CD8PD-1 T-cell subset, matching of TCRA-TCRB pairs by pairSEQ and single-cell RT-PCR, followed by testing of the TCRs for tumor-antigen specificity. Analysis of 12 fresh metastatic melanomas revealed that in 11 samples, up to 5 tumor-reactive TCRs were present in the 5 most frequently occurring clonotypes, which included reactivity against neoantigens. These data show the feasibility of developing a rapid, personalized TCR-gene therapy approach that targets the unique set of antigens presented by the autologous tumor without the need to identify their immunologic reactivity.

Original languageEnglish (US)
Pages (from-to)734-743
Number of pages10
JournalCancer immunology research
Volume4
Issue number9
DOIs
StatePublished - Sep 1 2016
Externally publishedYes

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ASJC Scopus subject areas

  • Immunology
  • Cancer Research

Cite this

Pasetto, A., Gros, A., Robbins, P. F., Deniger, D. C., Prickett, T. D., Matus-Nicodemos, R., Douek, D. C., Howie, B., Robins, H., Parkhurst, M. R., Gartner, J., Trebska-McGowan, K., Crystal, J. S., & Rosenberg, S. A. (2016). Tumor- and neoantigen-reactive T-cell receptors can be identified based on their frequency in fresh tumor. Cancer immunology research, 4(9), 734-743. https://doi.org/10.1158/2326-6066.CIR-16-0001