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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 and Caroline Arber

Key Points

  • c-MPL enables tumor-directed TCR+ T cells to become sequential killers by improving immune synapses, costimulation, and cytokine signals.

  • c-MPL activation improves in vivo persistence and antitumor function of adoptively transferred c-MPL+ TCR-transgenic T cells.

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-MPL+ 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.

  • Submitted February 17, 2017.
  • Accepted October 20, 2017.
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