Immune stromal components impede biological effectiveness of carbon ion therapy in a preclinical model of pancreatic ductal adenocarcinoma

Abstract

The tumor landscape of pancreatic ductal adenocarcinoma (PDAC) is refractory to conventional photon radiotherapy (RT) due to a fibrotic tumor microenvironment (TME) that promotes chronic hypoxia and reduced immune surveillance. The radiobiological factors unique to carbon ion radiotherapy (CIRT), such as high linear energy transfer (LET) and less dependence on oxygen, make it well-suited to overcome the PDAC TME. Here, we utilized clonal syngeneic KPC pancreatic tumor cell lines and tumors to examine this postulate and to identify underlying factors that impact the response of PDAC to CIRT. While KPC cell lines exhibited radiobiologic effectiveness (RBE) greater than 3, subcutaneous tumors in the mouse hind leg showed lower RBEs - 1.3 based on quintupling time - at a LET of 75 keV/m. Four days after CIRT, we observed widespread transcriptomic changes in the tumor immune microenvironment (TME), suggesting increased infiltration of anti-tumor immune cells, elevated expression of anti-tumor T cell cytokines, MHC class I molecules, and co-stimulatory signals. Fewer immunologic changes were observed following photon irradiation. By seven days after CIRT, tumor-supportive transcriptomic programs characterized by pro-tumor cytokines, M2 macrophages, and cancer-associated fibroblasts (CAFs) emerged, promoting resistance and limiting the durability of tumor growth delay. These findings suggest that CIRT may offer a favorable platform compared to conventional photon radiation therapy for combining with immunotherapies. Furthermore, these data highlight the risk of using in vitro survival data alone in treatment planning and indicate that underlying TME factors impact the response of PDAC in vivo.