Local delivery of SBRT and IL-12 to murine PDAC tumors modulates hematopoiesis

Standard of care radiotherapy and chemotherapy have shown limited efficacy in pancreatic ductal adenocarcinoma (PDAC). Immunotherapy has emerged as a promising treatment but has been hindered by systemic toxicities. A shift from systemic to localized delivery has reduced adverse effects and improved response rates in various cancers. However, the impact of tumor-targeted therapies on distant tissues, such as the bone marrow, remains underexplored. In a murine model of PDAC, we treated tumors with targeted stereotactic body radiation therapy (SBRT) and intratumoral interleukin-12 mRNA (IL-12). We evaluated tumor, blood, and bone marrow cells for therapy-induced changes over a period of 13 d to 13 months. Our results showed that while SBRT/IL-12 locally eradicated primary tumors, it also induced significant effects in the bone marrow. Early effects included acute lymphopenia in the blood and an immunostimulatory response in the bone marrow, leading to increased hematopoiesis. Long-term effects involved a reduction in hematopoietic stem cells (HSCs) and a shift towards a myeloid lineage, suggesting potential premature aging of the HSC population. These findings highlight the profound impact of localized SBRT/IL-12 therapy on distal bone marrow, emphasizing the need for further investigation into the long-term immunological consequences of localized cancer treatments.