miR-155 Regulates AML Tumor-Specific mRNA Vaccine Responses

Acute myeloid leukemia (AML) is a malignant clonal expansion of myeloid stem and progenitor cells, impeding normal hematopoiesis and culminating in bone marrow failure and mortality. Treatment with cytotoxic chemotherapy is often initially successful, but the development of chemo-resistant disease is common, indicating that new treatments are still needed. Recently, messenger RNA (mRNA) vaccines have emerged as potent inducers of antitumor immunity against solid tumors, yet their utility in the setting of AML, and the molecular mechanisms that govern their activity, are poorly defined. In our study, we demonstrate that microRNA-155 (miR-155) function in T cells is vital both for anti-tumor immunity against AML and mRNA vaccine efficacy against AML. Loss of miR-155 in both CD4+ and CD8+ T cells in conditional knockout mice (miR-155 fl/fl CD4+Cre) resulted in deficient antitumor immunity against syngeneic ovalbumin-expressing C1498 murine AML (C1498-OVA). Further, sterilizing immunity was provided by a tumor antigen-specific mRNA vaccine against C1498-OVA AML, but only if T cell-expressed miR-155 was present, in a process that included the differentiation of KLRG1+ CD8+ T cells. Single-cell RNA sequencing revealed distinct, miR-155-dependent transcriptome regulation of mRNA vaccine-responsive CD8+ T cells, which included a subset of genes that are regulated by miR-155 only during the mRNA vaccine response, indicating a novel context specific role for miR-155. These data indicate that T cell expressed miR-155 governs responses to tumor-specific mRNA vaccines by facilitating activation and differentiation cascades in CD8+ T cells and expanding memory CD8+ T cell reservoirs.