Advertisement

C-MPL provides tumor-targeted T cell receptor-transgenic T cells with co-stimulation 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, co-stimulation and cytokine signals

  • C-MPL activation improves in vivo persistence and anti-tumor function of adoptively transferred c-MPL+ TCR-transgenic T cells

Abstract

Adoptively transferred T cell receptor (TCR)-engineered T-cells depend on host-derived co-stimulation and cytokine signals for their full and sustained activation. However, in cancer patients both signals are frequently impaired. Hence, we developed a novel strategy that combines both essential signals in one transgene by expressing the non-lymphoid hematopoietic growth factor receptor c-MPL (myeloproliferative leukemia), the receptor for thrombopoietin (TPO), in T-cells. C-MPL signaling activates pathways shared with conventional co-stimulatory and cytokine receptor signaling. Thus, we hypothesized that host-derived TPO, present in the tumor microenvironment, or FDA-approved pharmacological c-MPL agonists 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 anti-tumor 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 anti-leukemic activity in vivo in a leukemia xenograft model. We identify the type I 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.