Thymic expression of a T-cell receptor targeting a tumor-associated antigen coexpressed in the thymus induces T-ALL

Yongzhi Cui, Masahiro Onozawa, Haven R. Garber, Leigh Samsel, Ziyao Wang, J. Philip McCoy, Sandra Burkett, Xiaolin Wu, Peter D. Aplan, Crystal L. Mackall

Research output: Contribution to journalArticlepeer-review

Abstract

T-cell receptors (TCRs) and chimeric antigen receptors recognizing tumor-associated antigens (TAAs) can now be engineered to be expressed on a wide array of immune effectors. Engineered receptors targeting TAAs have most commonly been expressed on mature T cells, however, some have postulated that receptor expression on immune progenitors could yield T cells with enhanced potency. We generated mice (survivin-TCRtransgenic [Sur-TCR-Tg]) expressing a TCR recognizing the immunodominant epitope (Sur20-28 ) of murine survivin during early stages of thymopoiesis. Spontaneous T-cell acute lymphoblastic leukemia (T-ALL) occurred in 100% of Sur-TCR-Tg mice derived from 3 separate founders. The leukemias expressed the Sur-TCR and signaled in response to the Sur20-28 peptide. In preleukemic mice, we observed increased cycling of doublenegative thymocytes expressing the Sur-TCR and increased nuclear translocation of nuclear factor of activated T cells, consistent with TCR signaling induced by survivin expression in the murine thymus. b2M2/2 Sur-TCR-Tg mice, which cannot effectively present survivin peptides on class I major histocompatibility complex, had significantly diminished rates of leukemia. We conclude that TCR signaling during the early stages of thymopoiesis mediates an oncogenic signal, and therefore expression of signaling receptors on developing thymocytes with specificity for TAAs expressed in the thymus could pose a risk for neoplasia, independent of insertional mutagenesis. (Blood. 2015;125(19):2958-2967)

Original languageEnglish (US)
Pages (from-to)2958-2967
Number of pages10
JournalBlood
Volume125
Issue number19
DOIs
StatePublished - 2015

Keywords

  • Thymic expression of signaling receptors targeting taas coexpressed in the thymus poses a risk for leukemogenesis
  • Thymocyte signaling via a transgenic survivin-reactive tcr induced t-all with 100% penetrance

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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