Targeting KRas-Driven Pancreatic Cancer via pIgR-Mediated Antibody Immunotherapy

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with limited treatment options and a five-year survival rate below 15%. Most cases are driven by KRAS mutations, particularly KRAS G12D, which are difficult to target effectively. Current potential therapies, including small molecule inhibitors, often show limited efficacy due to resistance mechanisms and a short half-life. This project explores antibody-based therapy using dimeric IgA antibodies that enter cancer cells through the polymeric immunoglobulin receptor (pIgR) to bind and inhibit KRas. We assessed how an IgA antibody designed to recognize mutant KRAS G12D (K-IgA) impacted tumor growth and immune responses in pancreatic cancer models. We found that treatment with K-IgA reduced cancer cell proliferation and increased immune cell infiltration as quantified by counting CD45⁺ total immune cells and/or CD8⁺ T cells. However, since pIgR levels vary within tumors (with a reduction of pIgR expression in full-blown carcinomas when compared to earlier-stage neoplasias), we also investigated the mechanisms that could enhance its expression. Our data suggests that inflammatory stimuli &ndash; such as <em>in vitro</em> co-cultures with M1 macrophages or <em>in vivo</em> injections of STING agonists &ndash; can boost expression of pIgR, potentially improving how well K-IgA is able to target tumor cells. From a nutritional standpoint, obesity is a state of chronic, low-grade inflammation. Knowing this, it may be worth attempting to determine if diet-induced obesity models inherently express higher pIgR levels, potentially priming them for optimal K-IgA therapy effectiveness. Next steps include further testing K-IgA combined with stimuli that improve pIgR expression in mouse models to evaluate its impact on tumor progression, immune activity, and toxicity, potentially offering a more effective path for treating pancreatic cancer.