C-MPL provides tumor-Targeted T-cell receptor-Transgenic T cells with costimulation and cytokine signals

Christopher D. Nishimura, Daniel A. Brenner, Malini Mukherjee, Rachel A. Hirsch, Leah Ott, Meng Fen Wu, Hao Liu, Olga Dakhova, Jordan S. Orange, Malcolm K. Brenner, Charles Y. Lin, Caroline Arber

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Adoptively transferred T-cell receptor (TCR)-engineered T cells depend on host-derived costimulation and cytokine signals for their full and sustained activation. However, in patients with cancer, both signals are frequently impaired. Hence, we developed a novel strategy that combines both essential signals in 1 transgene by expressing the nonlymphoid hematopoietic growth factor receptor c-MPL (myeloproliferative leukemia), the receptor for thrombopoietin (TPO), in T cells. c-MPL signaling activates pathways shared with conventional costimulatory and cytokine receptor signaling. Thus, we hypothesized that host-derived TPO, present in the tumor microenvironment, or pharmacological c-MPL agonists approved by the US Food and Drug Administration could deliver both signals to c-MPL-engineered TCR-Transgenic T cells. We found that c-MPL1 polyclonal T cells expand and proliferate in response to TPO, and persist longer after adoptive transfer in immunodeficient human TPO-Transgenic mice. In TCR-Transgenic T cells, c-MPL activation enhances antitumor function, T-cell expansion, and cytokine production and preserves a central memory phenotype. c-MPL signaling also enables sequential tumor cell killing, enhances the formation of effective immune synapses, and improves antileukemic activity in vivo in a leukemia xenograft model. We identify the type 1 interferon pathway as a molecular mechanism by which c-MPL mediates immune stimulation in T cells. In conclusion, we present a novel immunotherapeutic strategy using c-MPL-enhanced transgenic T cells responding to either endogenously produced TPO (a microenvironment factor in hematologic malignancies) or c-MPL-Targeted pharmacological agents.

Original languageEnglish (US)
Pages (from-to)2739-2749
Number of pages11
JournalBlood
Volume130
Issue number25
DOIs
StatePublished - Dec 21 2017

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Nishimura, C. D., Brenner, D. A., Mukherjee, M., Hirsch, R. A., Ott, L., Wu, M. F., Liu, H., Dakhova, O., Orange, J. S., Brenner, M. K., Lin, C. Y., & Arber, C. (2017). C-MPL provides tumor-Targeted T-cell receptor-Transgenic T cells with costimulation and cytokine signals. Blood, 130(25), 2739-2749. https://doi.org/10.1182/blood-2017-02-769463