T-cell miR-155 regulates the response to tumor-specific mRNA vaccines in a murine model of acute myeloid leukemia
Abstract
Abstract Acute myeloid leukemia (AML) is a malignant clonal expansion of myeloid progenitor cells that impedes normal hematopoiesis and culminates in bone marrow failure and death. The development of chemoresistant disease in response to first-line chemotherapies is common and indicates a need for new therapies. Tumor-specific mRNA vaccines have emerged as potent inducers of cellular immunity against solid tumors, yet their utility in targeting AML and the specific mechanisms that govern their broader activity remain poorly defined. Here, we demonstrate that microRNA-155 (miR-155) within T cells is vital for host anti-leukemia responses at baseline, and for mRNA vaccine–elicited cellular responses against AML. Loss of miR-155 in T cells in conditional knockout (TCKO) mice (miR-155 fl/fl CD4+Cre) results in deficient antitumor immunity against syngeneic ovalbumin-expressing C1498 murine AML (C1498-OVA). T cell–intrinsic miR-155 is required for terminal differentiation of short-lived effector KLRG1+ CD8+ T cells, thereby providing protective immunity induced by a tumor Ag–specific mRNA vaccine against C1498-OVA AML. Single-cell RNA sequencing reveals distinct miR-155–dependent transcriptomic regulation during the mRNA vaccine response. including changes indicative of a failure to appropriately respond to IFN-γ signaling in miR-155 TCKO CD8+ T cells. Notably, we identify a subset of genes modulated by miR-155 in CD8+ T cells specific to response to mRNA vaccination, indicating a novel and context-specific role for miR-155 in regulating the immune response to mRNA–lipid nanoparticle therapeutics. Together, these data indicate T cell–expressed miR-155 is a master regulator of intrinsic cellular immunity to AML and promotes tumor-specific mRNA vaccine responses.
Article Details
Journal Info
The Journal of Immunology
American Association of Immunologists
Authors (18)
Benjamin Battistone
Department of Pathology, Division of Microbiology and Immunology, University of Utah , Salt Lake City, UT,
Arevik Ghazaryan
Department of Pathology, Division of Microbiology and Immunology, University of Utah , Salt Lake City, UT,
William W Tang
Department of Pathology, Division of Microbiology and Immunology, University of Utah , Salt Lake City, UT,
Zekıye Büşra Ağir
Izmir Institute of Technology Department of Molecular Biology and Genetics , Izmir,
Jacob Tantalla
Department of Pathology, Division of Microbiology and Immunology, University of Utah , Salt Lake City, UT,
Jacob Thompson
Department of Pathology, Division of Microbiology and Immunology, University of Utah , Salt Lake City, UT,
Kaylyn M Bauer
Department of Pathology, Division of Microbiology and Immunology, University of Utah , Salt Lake City, UT,
Cindy Barba
Department of Pathology, Division of Microbiology and Immunology, University of Utah , Salt Lake City, UT,
Morgan Nelson
Department of Pathology, Division of Microbiology and Immunology, University of Utah , Salt Lake City, UT,
Van T B Tran
Department of Pathology, Division of Microbiology and Immunology, University of Utah , Salt Lake City, UT,
Liam O’Malley
Department of Pathology, Division of Microbiology and Immunology, University of Utah , Salt Lake City, UT,
Quynh Ngo
Department of Pathology, Division of Microbiology and Immunology, University of Utah , Salt Lake City, UT,
Colton Hernandez
Department of Pathology, Division of Microbiology and Immunology, University of Utah , Salt Lake City, UT,
Amber Thibeaux
Department of Pathology, Division of Microbiology and Immunology, University of Utah , Salt Lake City, UT,
Hüseyin Atakan Ekiz
Izmir Institute of Technology Department of Molecular Biology and Genetics , Izmir,
Warren P Voth
Department of Pathology, Division of Microbiology and Immunology, University of Utah , Salt Lake City, UT,
Dinesh S Rao
Department of Pathology and Laboratory Medicine, University of California Los Angeles , Los Angeles, CA,
Ryan M O’Connell
Department of Pathology, Division of Microbiology and Immunology, University of Utah , Salt Lake City, UT,