Restoring tumor immunogenicity with dendritic cell reprogramming

Abstract

PFIZER RESEARCH AWARDS 2024

Scientific Background

Cancer cells develop mechanisms to evade the immune system, including immunosuppression, intratumor heterogeneity, exclusion of immune cells from the tumor microenvironment, and downregulation of antigen presentation. Immunotherapies, such as immune checkpoint blockade (ICB) and adoptive T cell therapies, changed paradigms in cancer treatment. However, existing immunotherapies show limited efficacy in some patients. Notably, studies report that the success of ICB depends on tumor immunogenicity and antigen presentation to promote efficient CD8+ T cell priming.

Cellular reprogramming is the process of changing cell fate through epigenetic rewiring of a somatic cell type and the imposition of another desired cell identity, usually mediated by transcription factors (TFs). In cancer, cell fate reprogramming has been shown to lead to the disruption of oncogenic pathways and decreased tumorigenicity, but this strategy is limited by the requirement of reprogramming most cancer cells in the tumor. Ideally, a reprogramming-based strategy would be combined with an immunotherapeutic approach that has the potential to target immune activation while decreasing tumorigenicity. Immune activation greatly depends on type 1 conventional dendritic cells (cDC1), which cross-present tumor antigens to CD8+ T cells, prompting antitumor immunity. In fact, the presence of cDC1 in tumors correlates with better survival and response to immunotherapy. Overexpressing the three TFs PU.1, IRF8, and BATF3 (referred to as PIB) promotes direct reprogramming of mouse and human fibroblasts into immunogenic cDC1 (Rosa et al., 2018; 2022, Science Immunology). The current study (Zimmermannova et al., 2023, Science Immunology) aimed at reprogramming cancer cells into professional, cDC1-like antigen-presenting cells (APCs) to counteract tumor immune evasion and induce tumor immunogenicity.