Immune stromal components impede biological effectiveness of carbon ion therapy in a preclinical model of pancreatic ductal adenocarcinoma [bulk RNA-seq]

Pancreatic ductal adenocarcinoma (PDAC) often invades blood vessels, thrives in hypoxic conditions, and supports an immune microenvironment that is highly resistant to treatment. Carbon ion radiation therapy (CIRT) has potential to benefit patients with PDAC, since oxygen enhancement is not required due to high linear energy transfer (LET) radiation and the spread-out Bragg peak permits sparing of adjacent normal tissues. However, we found that underlying factors impact the response of PDAC to CIRT. Clonal syngeneic KPC pancreatic tumors modeled a treatment-resistant microenvironment and showed limited response to CIRT in vivo. While KPC cell lines exhibited radiobiologic effectiveness (RBE) greater than 3, subcutaneous tumors in the mouse hind leg showed much lower RBEs - 1.3 based on tripling time and 1.7 based on quintupling time - at a LET of 75 keV/μm. Four days after CIRT, we observed widespread transcriptomic changes in the tumor immune microenvironment (TME), including 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.