Upon intratumoral delivery of a 1:1 mix of tumor-specific T cells, TILs, or CAR T cells electroporated with single-chain IL-12 or a mutant form of IL-18 that is not bound and is downregulated by a decoy receptor (DRIL18), Olivera and Bolanos et al. observed synergistic efficacy and rejection of treated and distant tumors. The transduced cytokines induced changes in the O-glycosylation profile of cell surface proteins forming E-selectin ligands important for efficacy on distant tumors, enhanced T cell glucose metabolism and mitochondrial respiration, increased cytokine production, and upregulated miR155 control of immunosuppressive target genes, boosting the efficacy of intratumoral T cell therapy.
Contributed by Ute Burkhardt
ABSTRACT: Interleukin-12 (IL-12) gene transfer enhances the therapeutic potency of adoptive T cell therapies. We previously reported that transient engineering of tumor-specific CD8 T cells with IL-12 mRNA enhanced their systemic therapeutic efficacy when delivered intratumorally. Here, we mix T cells engineered with mRNAs to express either single-chain IL-12 (scIL-12) or an IL-18 decoy-resistant variant (DRIL18) that is not functionally hampered by IL-18 binding protein (IL-18BP). These mRNA-engineered T cell mixtures are repeatedly injected into mouse tumors. Pmel-1 T cell receptor (TCR)-transgenic T cells electroporated with scIL-12 or DRIL18 mRNAs exert powerful therapeutic effects in local and distant melanoma lesions. These effects are associated with T cell metabolic fitness, enhanced miR-155 control on immunosuppressive target genes, enhanced expression of various cytokines, and changes in the glycosylation profile of surface proteins, enabling adhesiveness to E-selectin. Efficacy of this intratumoral immunotherapeutic strategy is recapitulated in cultures of tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T cells on IL-12 and DRIL18 mRNA electroporation.
Author Info: (1) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain. (2) Progr
Author Info: (1) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain. (2) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain. (3) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain. (4) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain. (5) Laboratorio de Glicmica Funcional y Molecular, Instituto de Biologa y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Cientficas y Tcnicas (CONICET), Ciudad de Buenos Aires 1428, Argentina. (6) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain. (7) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain. (8) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain. (9) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain. (10) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain. (11) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain; Centro de Investigacin Biomdica en Red de Cncer (CIBERONC), Madrid, Spain. (12) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain; Centro de Investigacin Biomdica en Red de Cncer (CIBERONC), Madrid, Spain. (13) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain. (14) Department of Hematology and Oncology, Hospital Clinic, Institut d'Investigacions Biomdiques August Pi iSunyer (IDIBAPS), Barcelona, Spain. (15) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain; Centro de Investigacin Biomdica en Red de Cncer (CIBERONC), Madrid, Spain. (16) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain; Centro de Investigacin Biomdica en Red de Cncer (CIBERONC), Madrid, Spain. (17) Laboratorio de Glicomedicina, Instituto de Biologa y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Cientficas y Tcnicas (CONICET), Ciudad de Buenos Aires 1428, Argentina; Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad de Buenos Aires 1428, Argentina. (18) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain. (19) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain; Centro de Investigacin Biomdica en Red de Cncer (CIBERONC), Madrid, Spain; Department of Immunology and Immunotherapy, Clnica Universidad de Navarra, Pamplona, Spain. Electronic address: imelero@unav.es.
