Abstract
The low overall survival rate of patients with pancreatic cancer has driven research to seek a new therapeutic protocol. Radiotherapy (RT) is frequently an option in the neoadjuvant or palliative settings for pancreatic cancer treatment. This study explored the effect of RT protocols on the tumor microenvironment (TME) and their consequent impact on anti-programmed cell death ligand-1 (PD-L1) therapy. Using a murine orthotopic pancreatic tumor model, UN-KC-6141, RT-disturbed TME was examined by immunohistochemical staining. The results showed that ablative RT is more effective than fractionated RT at recruiting T cells. On the other hand, fractionated RT induces more myeloid-derived suppressor cell infiltration than ablative RT. The RT-disturbed TME presents a higher perfusion rate per vessel. The increase in vessel perfusion is associated with a higher amount of anti-PD-L1 antibody being delivered to the tumor. Animal survival is increased by anti-PD-L1 therapy after ablative RT, with 67% of treated animals surviving more than 30 days after tumor inoculation compared to a median survival time of 16.5 days for the control group. Splenocytes isolated from surviving animals were specifically cytotoxic for UN-KC-6141 cells. We conclude that the ablative RT-induced TME is more suited than conventional RT-induced TME to combination therapy with immune checkpoint blockade.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most challenging cancers
The results showed that the ability of RT to cause tumor-shrinkage was dose-dependent, and the SHD-RT protocol had a similar effect on tumor shrinkage as the fractionated radiation therapy (F-RT) protocol with the same biological effective dose (BED) (Figure 1)
This study demonstrated that a high dose of RT could alter the tumor microenvironment (TME) of the UN-KC-6141 tumor to favor T cell infiltration and the delivery of anti-programmed cell death ligand-1 (PD-L1) antibody
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most challenging cancers. According to SEER (Surveillance, Epidemiology, and End Result), the 5-year overall survival (5YOS) rate of many cancers has been significantly improved [1], but the 5YOS for PDAC is less than 10%, which is the lowest of all cancers and has not improved in the last ten years [2]. PDAC frequently develops a unique tumor microenvironment (TME) composed of the high density of stromal cells and multiple immunosuppressive mechanisms [16,17,18]. Due to these multiple obstacles, an immune boost to overcome the immunosuppressive pancreatic TME is critically needed. In this regard, encouraging results have been reported in recent clinical trials (NCT02588443) of a combination of anti-CD40 with Nab-paclitaxel and gemcitabine to target different stromal components
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