Abstract
BackgroundAlthough 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.MethodsWe 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.ResultsWe 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.ConclusionsttIL-12 when combined with surgery led to conversion to the IFNγHiCD8HiFOXP3LowCD33Low immune profile, eliminated relapse and metastasis, and prolonged overall survival.
Highlights
Communication between tumor cells and the associated immune system is pivotal for tumor metastasis, relapse, and progression
We developed an Interleukin 12 (IL-12) that targets cell-surface vimentin (CSV), a protein found on the surfaces of tumor cells across tumor types, especially metastatic tumors [19, 20]
By analyzing The Cancer Genome Atlas (TCGA) data across different human tumors for markers of immunostimulatory interferongamma (IFNγ)–positive CD8+ cytotoxic T cells and immunosuppressive T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs), we found that the immune profile IFNγHiCD8aHiFOXP3LowCD33Low predicted excellent patient outcome across different tumor types
Summary
Communication between tumor cells and the associated immune system is pivotal for tumor metastasis, relapse, and progression. Since Rudolf Virchow first proposed the link between tumorigenesis and chronic inflammation, The primary immune cells in tumors are tumorinfiltrating lymphocytes, myeloid cells, and macrophages, Zhao et al Journal for ImmunoTherapy of Cancer (2019) 7:154 which consist of both immunostimulatory populations and immunosuppressive populations. Immunosuppressive populations, including myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and tumor-associated macrophages, are mobilized during tumorigenesis and relapse. After infiltrating into developing tumors, MDSCs promote tumor vascularization and disrupt immunosurveillance, including M1 macrophage polarization, antigen presentation [10], T cell activation [11], and NK cell cytotoxicity [12]. 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
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