TY - JOUR
T1 - C-MPL provides tumor-Targeted T-cell receptor-Transgenic T cells with costimulation and cytokine signals
AU - Nishimura, Christopher D.
AU - Brenner, Daniel A.
AU - Mukherjee, Malini
AU - Hirsch, Rachel A.
AU - Ott, Leah
AU - Wu, Meng Fen
AU - Liu, Hao
AU - Dakhova, Olga
AU - Orange, Jordan S.
AU - Brenner, Malcolm
AU - Lin, Charles Y.
AU - Arber, Caroline
N1 - Funding Information:
Conflict-of-interest disclosure: C.Y.L. receives royalty payments from Syros Pharmaceuticals and has sponsored travel from Novartis Institute for Biomedical Research; C.A. receives royalty payments from Cell Medica. The remaining authors declare no competing financial interest.
Funding Information:
M.M. is supported by a National Institutes of Health, National Cancer Institute SPORE in Lymphoma career development award P50CA126752; C.Y.L. is supported by the Cancer Prevention and Research Institute of Texas (CPRIT, RR150093) and by the National Institutes of Health, National Cancer Institute (1R01CA215452-01); C.A. is supported by a Leukemia and Lymphoma Society Translational Research Program grant and a CPRIT Individual Investigator Research Award (RP160345). We also appreciate the support of shared resources in the National Institutes of Health, National Cancer Institute Cancer Center support grant P30CA125123.
Publisher Copyright:
© 2017 by The American Society of Hematology.
PY - 2017/12/21
Y1 - 2017/12/21
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85039153675&partnerID=8YFLogxK
U2 - 10.1182/blood-2017-02-769463
DO - 10.1182/blood-2017-02-769463
M3 - Article
C2 - 29079582
AN - SCOPUS:85039153675
VL - 130
SP - 2739
EP - 2749
JO - Blood
JF - Blood
SN - 0006-4971
IS - 25
ER -