Regulation of antigen presenting cells in the tumor microenvironment by retinoic acid

Project Summary and Abstract Evading immune responses is a hallmark of cancer. Solid tumors create a microenvironment that prevent detection of tumor cells by the immune system and block anti-tumor T cell activity. The therapeutic value of targeting immune evasion pathways is highlighted by the recent clinical successes of alleviating T cell suppression via immune checkpoint blockade in a handful of solid tumors. However, anti-tumor T cells are not generated in most solid tumors, which greatly limits the application of checkpoint blockade. One reason for this is the paucity and dysfunction of antigen-presenting dendritic cells (APCs) in solid tumor microenvironment (TME), but the underlying pathways are poorly understood. Our long-term goal is to discover and delineate pathways that control APC recruitment, differentiation, and function in TME. The overarching goal is to target these pathways to enhance antigen presentation and adaptive immune responses for solid tumor immunotherapy. I have previously developed powerful genetically engineered mouse models of sarcomas, a type of lethal solid tumor, as well as murine models to study antigen-presenting cells. Using these tools, we have recently discovered that retinoic acid (RA) produced by tumor cells act on tumor-infiltrating monocytes to prevent their differential into dendritic cells, instead promoting their differentiation into immunosuppressive macrophages. Furthermore, we have found that the cytokine IL13 promotes RA production in tumor cells. Based on these findings, our central hypothesis is that IL13-induced RA production by tumor cells prevents the generation of monocyte-derived dendritic cells in TME. Our three specific aims will; delineate the mechanism by which RA affects monocyte differentiation and antigen presentation (Aim 1), uncover the source of IL13 in TME and its impact on anti-tumor immune responses (Aim 2), and examine the potential of targeting IL13 and RA signaling for tumor immunotherapy (Aim 3). This work will have significant impact on our understanding of immunomodulation in solid tumors and extend our understanding of how tissue metabolites can control monocyte differentiation. Our findings will also open new avenues for solid tumor immunotherapy based on targeting RA signaling and APCs. The clinical implications are particularly impactful for sarcomas where current treatment options are extremely limited. Our work is innovative because it will open new avenues of research examining the role of retinoid signaling in APC differentiation and tumor immunity. There are many commercially available small molecule inhibitors of RA signaling, but none has been used for therapeutic purposes. Therefore, our work will not only provide a proof of concept for RA blockade in tumor immunotherapy, but is also amenable to rapid human translation.