Reprogramming leukemia cells into antigen presenting cells as a novel cancer vaccination immunotherapy

Abstract

Abstract B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematopoietic neoplasm characterized by recurrent genetic lesions resulting in malignant transformation. Despite an arrest in B cell maturation, human B-ALL blasts retain the capacity for reprogramming to the myeloid lineage. To test the therapeutic implications of reprogramming, we generated murine models of B-ALL capable of myeloid lineage reprogramming via ectopic expression of CEBPα and PU.1. Once reprogrammed, B-ALL cells acquired an APC phenotype and stimulated antigen-specific T cells. In vivo B-ALL reprogramming in immunodeficient mice led to a modest survival benefit, however, reprogramming in immunocompetent mice led to tumor eradication and protection from subsequent re-challenge, demonstrating successful generation of durable, systemic, and curative immunity. This therapeutic benefit is dependent on the presence of both CD4+ and CD8+ T cells, and characterized by an increased frequency of bone marrow-infiltrating T cells and oligoclonal T cell expansion. Moreover, local myeloid reprogramming of a primary tumor drove systemic immune activation and eradication of distant, non-reprogrammed lesions. Our data suggests that B-ALL cells reprogrammed to the myeloid lineage are potent APCs capable of presenting tumor-associated antigens, and in vivo reprogramming elicits robust, durable, tumor-eradicating, and systemic T cell-mediated immunity. Recent efforts have further identified sarcoma and carcinoma models amenable to myeloid-lineage reprogramming. Thus, reprogramming of malignant cells into APCs represents a novel immunotherapeutic strategy with potential clinical utility in the treatment of a broad array of human malignancies.