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

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Abstract Background Standard of care therapies such as radiotherapy and chemotherapy have shown little efficacy against pancreatic ductal adenocarcinoma (PDAC). Immunotherapy is a newly emerging form of treatment that has shown promise; however, toxic systemic effects resulted in limited use in the clinic. Shifting from systemic to local delivery of cancer therapeutics reduces adverse systemic effects and increases response rates in multiple malignancies. Importantly, the effects of tumor-targeted therapies on distal tissues, such as the bone marrow, have not been thoroughly investigated. Methods Using a murine model of PDAC, we treated tumors with targeted stereotactic body radiation therapy (SBRT) and intratumoral interleukin-12 (IL-12). 13 days-13 months after tumor injection, the cells in the tumor, blood, and bone marrow were analyzed for therapy-induced changes. Hematopoietic cell numbers and lymphocytes were quantified by flow cytometry, and cytokine levels were quantified by enzyme-linked immunosorbent assays (ELISAs). Results We demonstrated that although SBRT/IL-12 delivered locally to PDAC tumors successfully eradicated primary disease, it also induced significant acute and long-term effects in the bone marrow. Within days of intratumoral SBRT/IL-12 treatment, we observed acute lymphopenia in the blood, accompanied by an immunostimulatory response in the bone marrow characterized by an increase in hematopoiesis. Long-term effects included a decrease in hematopoietic stem cells (HSCs) and skewing toward a myeloid lineage bias, which could indicate premature aging of the HSC population. Conclusions These findings demonstrate that despite being locally delivered to the tumor, SBRT/IL-12 therapy exerts significant effects on the distal bone marrow, reinforcing the need for further investigations into the long-term systemic immunological outcomes of localized cancer treatments. Key Messages What is already known on this topic : Systemic cancer therapies used to combat pancreatic ductal adenocarcinoma (PDAC) often induce toxic systemic effects. Local delivery of radiation and immunotherapy reduces adverse effects; however, the systemic spread of these therapies and the resulting effects on distal tissues such as the bone marrow have yet to be elucidated. What this study adds : Intratumoral delivery of stereotactic body radiation therapy (SBRT) and interleukin-12 (IL-12) augment hematopoiesis in the bone marrow soon after treatment and induce long-term alterations in the hematopoietic stem cells (HSCs). These effects are mainly a result of IL-12 that is transiently increased in the bone marrow after treatment. How this study might affect research, practice, or policy : Targeted SBRT/IL-12 therapy induces long-term systemic effects on the bone marrow, indicating the need for further investigation of the systemic spread of locally delivered therapeutics.

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