PT - JOURNAL ARTICLE AU - Qingnan Zhao AU - Jiemiao Hu AU - Abhisek Mitra AU - Jeffry Cutrera AU - Wendong Zhang AU - Zhongting Zhang AU - Jun Yan AU - Xueqing Xia AU - Kris Michael Mahadeo AU - John Andrew Livingston AU - Richard Gorlick AU - Shulin Li TI - Tumor-targeted IL-12 combined with tumor resection yields a survival-favorable immune profile AID - 10.1186/s40425-019-0631-z DP - 2019 Dec 01 TA - Journal for ImmunoTherapy of Cancer PG - 154 VI - 7 IP - 1 4099 - http://jitc.bmj.com/content/7/1/154.short 4100 - http://jitc.bmj.com/content/7/1/154.full SO - J Immunother Cancer2019 Dec 01; 7 AB - Background Although accumulated evidence provides a strong scientific premise for using immune profiles to predict survival in patients with cancer, a universal immune profile across tumor types is still lacking, and how to achieve a survival-associated immune profile remains to be evaluated.Methods We analyzed datasets from The Cancer Genome Atlas to identify an immune profile associated with prolonged overall survival in multiple tumor types and tested the efficacy of tumor cell-surface vimentin–targeted interleukin 12 (ttIL-12) in inducing that immune profile and prolonging survival in both mouse and patient-derived xenograft tumor models.Results We identified an immune profile (IFNγHiCD8HiFOXP3LowCD33Low) associated with prolonged overall survival across several human tumor types. ttIL-12 in combination with surgical resection of the primary tumor transformed tumors to this immune profile. Intriguingly, this immune profile transformation led to inhibition of metastasis and to prolonged survival in both mouse and patient-derived xenograft malignant models. Wild-type IL-12 combined with surgery was significantly less effective. In the IL-12–sensitive C3H mouse strain, in fact, wild-type IL-12 and surgery resulted in shorter overall survival than in mice treated with control pDNA; this surprising result is believed to be attributable to IL-12 toxicity, which was absent in the mice treated with ttIL-12. The ttIL-12–induced immune profile associated with longer overall survival was also associated with a greater accumulation of CD8+ T cells and reduced infiltration of regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. The underlying mechanism for this transformation by ttIL-12 treatment was induction of expression of CXCL9 and reduction of expression of CXCL2 and CCL22 in tumors.Conclusions ttIL-12 when combined with surgery led to conversion to the IFNγHiCD8HiFOXP3LowCD33Low immune profile, eliminated relapse and metastasis, and prolonged overall survival.Qingnan Zhao and Jiemiao Hu contributed equally to this work.Abbreviations:Arg1Arginase 1CCL22CC-chemokine ligand 22CCL5CC-chemokine ligand 5CSVCell-surface vimentinCTLA4Cytotoxic T lymphocyte-associated antigen 4CtrlControl pDNACXCL10CXC-chemokine ligand 10CXCL2CXC-chemokine ligand 2CXCL9CXC-chemokine ligand 9CXCR4CXC-chemokine receptor 4httIL-12Human ttIL-12hwtIL-12Human wtIL-12IFNγInterferon-gammaIL-10Interleukin-10IL-12Interleukin-12IL-35Interleukin-35MDSCsMyeloid-derived suppressor cellsNKNatural killerNKG2DNatural killer group 2DOSOverall survivalPBMCsPeripheral blood mononuclear cellspCCL22CCL22 plasmid DNApCXCL2CXCL2 plasmid DNAPD-1Programmed death 1 receptorPD-L1PD-1 ligandpDNAPlasmid DNAPDXPatient-derived xenograftSDStandard deviationTCGAThe Cancer Genome AtlasTGF-βTransforming growth factor betaTregsRegulatory T cellsttIL-12 + SttIL-12 treatment combined with surgeryttIL-12Tumor cell surface vimentin–targeted interleukin 12wtIL-12 + SwtIL-12 treatment combined with surgerywtIL-12Wild-type interleukin 12