Restoring tumor immunogenicity with dendritic cell reprogramming.

Decreased antigen presentation contributes to the ability of cancer cells to evade the immune system. We used the minimal gene regulatory network of type 1 conventional dendritic cells (cDC1) to reprogram cancer cells into professional antigen-presenting cells (tumor-APCs). Enforced expression of the transcription factors PU.1, IRF8, and BATF3 (PIB) was sufficient to induce the cDC1 phenotype in 36 cell lines derived from human and mouse hematological and solid tumors. Within 9 days of reprogramming, tumor-APCs acquired transcriptional and epigenetic programs associated with cDC1 cells. Reprogramming restored the expression of antigen presentation complexes and costimulatory molecules on the surfaces of tumor cells, allowing the presentation of endogenous tumor antigens on MHC-I and facilitating targeted killing by CD8+ T cells. Functionally, tumor-APCs engulfed and processed proteins and dead cells, secreted inflammatory cytokines, and cross-presented antigens to naïve CD8+ T cells. Human primary tumor cells could also be reprogrammed to increase their capability to present antigen and to activate patient-specific tumor-infiltrating lymphocytes. In addition to acquiring improved antigen presentation, tumor-APCs had impaired tumorigenicity in vitro and in vivo. Injection of in vitro generated melanoma-derived tumor-APCs into subcutaneous melanoma tumors delayed tumor growth and increased survival in mice. Antitumor immunity elicited by tumor-APCs was synergistic with immune checkpoint inhibitors. Our approach serves as a platform for the development of immunotherapies that endow cancer cells with the capability to process and present endogenous tumor antigens.

The impact of immunopeptidomics: From basic research to clinical implementation.

The immunopeptidome is the set of peptides presented by the major histocompatibility complex (MHC) molecules, in humans also known as the human leukocyte antigen (HLA), on the surface of cells that mediate T-cell immunosurveillance. The immunopeptidome is a sampling of the cellular proteome and hence it contains information about the health state of cells. The peptide repertoire is influenced by intra- and extra-cellular perturbations - such as in the case of drug exposure, infection, or oncogenic transformation. Immunopeptidomics is the bioanalytical method by which the presented peptides are extracted from biological samples and analyzed by high-performance liquid chromatography coupled to tandem mass spectrometry (MS), resulting in a deep qualitative and quantitative snapshot of the immunopeptidome. In this review, we discuss published immunopeptidomics studies from recent years, grouped into three main domains: i) basic, ii) pre-clinical and iii) clinical research and applications. We review selected fundamental immunopeptidomics studies on the antigen processing and presentation machinery, on HLA restriction and studies that advanced our understanding of various diseases, and how exploration of the antigenic landscape allowed immune targeting at the pre-clinical stage, paving the way to pioneering exploratory clinical trials where immunopeptidomics is directly implemented in the conception of innovative treatments for cancer patients.