Colorectal cancer mRNA therapy focusing on the immune checkpoint ST2

Colorectal cancer (CRC) ranks 3rd in terms of new cases in Flanders and accounts for 1 in 10 cancer-related deaths.
Immune checkpoint blockade (ICB) aims to rally the immune system’s ability to eliminate CRC cells but has been unsatisfactory in the majority of CRC patients. mRNA immunization could synergize with ICB. Preclinical and clinical studies show that mRNA immunization activates T cells, a necessity for ICB success. Our preliminary data
show that immunization depending on tumor antigen presenting dendritic cells (DCs) is impeded by the receptor STimulation 2 (ST2, interleukin 1 receptor-like 1 [IL1RL1]) and its ligand interleukin 33 (IL33) and that ST2 upregulation occurs following mRNA delivery to human and mouse DCs. The COLORNA project therefore aims to understand the impact of ST2/IL33 on mRNA immunization in CRC, as this opens opportunities to improve immunotherapy outcome. We will study (soluble) ST2 and IL33 expression by DCs transfected with mRNA, using in vitro generated DCs and lymph node (LN)- resident DCs of human origin as well as LN- and tumor-resident DCs of wild type, ST2 or IL33 knockout (KO) mice. We will study the DCs’ transcriptome, phenotype and T-cell activating capacity following mRNA transfection and how ST2/IL33 impact hereon, including the use of ST2/IL33 blocking
monoclonal antibodies (mAbs). We will also study how ST2/IL33 impact on the outcome of mRNA immunization using (orthotopic) CRC models in transgenic (ST2KO and/or IL33 KO) mice. As a result, the COLORNA project will validate IL33/ST2 in CRC as a therapeutic target and its role in DC an mRNA immunization. The impact of the COLORNA project could be high. mRNA vaccination has attracted a wide interest in the cancer immunotherapy field, which has been reinforced by the success of COVID-19 vaccines. Blocking ST2/IL33 to further improve mRNA therapeutic cancer vaccines and as a result also ICB therapy is a strategy that could be translated to clinical trials. To
date, mAbs impeding ST2/IL33 signaling are clinically evaluated in diseases such as asthma (i.e., Tozorakimab [IL33], Astegolimab [ST2]). These could be repurposed for cancer immunotherapy.