Harnessing the Immunomodulatory Potential of Radiofrequency Ablation to Improve Therapeutic Outcomes in Pancreatic Ductal Adenocarcinoma

Bhumi Maniyar, BS (Advisor: Kendra Carmon, PhD)

          With its thick desmoplastic stroma, severe immunological suppression, and resistance to standard treatments, pancreatic ductal adenocarcinoma (PDAC) continues to rank among the most lethal cancers. The need for innovative therapeutic approaches is highlighted by the tumor microenvironment's (TME) critical role in promoting disease development and reducing the effectiveness of treatment. A promising locoregional treatment that can induce tumor necrosis and modify the TME is endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA). However, there is still minimal understanding around its wider impact on stromal remodeling and immunological activation. This study investigates the immunomodulatory effects of RFA, both in a clinical setting combined with neoadjuvant chemotherapy and in combination with immune checkpoint blockade, using a syngeneic pancreatic cancer mouse model. We demonstrate that when RFA is combined with an αPD-L1 treatment, it causes both local and systemic immune activation, improving Granzyme B+ cell infiltration, boosting collagen deposition, reducing immunosuppressive cytokine signaling, and promoting an abscopal response in distant, untreated tumors. In accordance with these results, RFA may help the immune system to overcome PDAC's innate immunotherapy resistance. To further analyze the clinical significance of these results, we used human PDAC biospecimens to examine the effects of EUS-RFA in conjunction with chemotherapy in the neoadjuvant setting. Apoptotic cell death as measured by cleaved caspase-3 expression, changes in collagen deposition, expression of macrophage migration inhibitory factor (MIF) levels, and changes in hypoxia-inducible factor 2-alpha (HIF2α) expression were among the important components of the TME that were examined. Mechanistic insights into how EUS-RFA may improve chemotherapeutic efficacy in PDAC are provided by our data, which show notable alterations in several tumor-associated variables post-RFA. Together, this study demonstrates how RFA can be used in conjunction with immunotherapy and chemotherapy to change the PDAC microenvironment, boost anti-tumor immunity, and enhance therapeutic results. These findings lay the groundwork for developing innovative therapeutic approaches and refining combination treatment strategies for this extremely resistant cancer.

Advisory Committee:

• Kendra Carmon, PhD, Chair
• Jennifer Bailey, PhD
• Ali Azhdarinia, PhD
• Anirban Maitra, PhD
• Florencia McAllister, PhD
• Kyle Poulsen, PhD

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