Ablative Radiotherapy Reprograms the Tumor Microenvironment of a Pancreatic Tumor in Favoring the Immune Checkpoint Blockade Therapy

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.

Locoregional therapies and their effects on the tumoral microenvironment of pancreatic ductal adenocarcinoma

“…Some data suggest that the combination of RT with immunotherapy could be a future approach to overcome this limitation. In a study by Lee et al [ 57 ], the combination of SHD-RT with anti-PD1 increased the delivery of anti-PD1 in a murine orthotopic mouse model of PDAC (UN-KC-6141), which is consistent with the increased tumor perfusion observed in vivo following RT. The survival of mice receiving a combined treatment of anti-PD1/SHD-RT was significantly improved compared to that of mice receiving anti-PD1 or SHD-RT alone.…”

“…In a rodent model of pancreatic tumor, a single high dose (SHD) of radiation led to temporary vascular dysfunction along with enhanced expression of HIF-1, which could be restored after 14 d. However, vascular permeability was higher in irradiated tumors 14 d after RT[ 56 ]. Similarly, a study by Lee et al [ 57 ] evaluated the effect of an SHD of radiation vs a fractionated regimen of radiation, which showed increased perfusion ability of tumor vessels following SHD, whereas fractionated RT had no effect. Mechanisms were further studied and showed that vessels treated with SHD-RT had lower pericyte coverage; increased vessel perfusion could therefore be due to an increased leakage of immature vessels, and the surviving vessels after SHD-RT might favor the penetration of small molecule drugs.…”

“…In vitro studies showed that human lung fibroblasts develop an irreversible senescent phenotype after exposure to a radiation dose higher than 10 Gy, while lower doses induced reversible DNA damage without growth arrest[ 51 , 62 , 63 ]. Senescent fibroblasts can release proteolytic enzymes, cytokines, growth factors, and ROS, creating a protumorogenic environment[ 49 , 57 , 64 ]. Similarly, in vitro , the coculture of ionizing radiation-exposed CAFs with pancreatic cancer cells enhanced the invasion-promoting capacity of CAFs, induced a high secretion of CXCL12 (a chemokine implicated in hematopoietic stem cell maintenance and cell migration) by CAFs, and promoted pancreatic cell migration, invasion, and epithelial-mesenchymal transition[ 65 ].…”

“…In a murine orthotopic pancreatic cancer model, irradiated tumors displayed increased CD8+ and CD4+ cells, with a high single dose of RT being more efficient in recruiting CD8+ T lymphocytes than fractionated RT. However, fractionated RT induced more infiltration of myeloid-derived suppressor cells than high-dose RT[ 57 ]. In vitro , RT increased the expression of PDL-1 in a Jack/stat1-dependent manner[ 70 ].…”

Destruction of Tumor Microenvironment as a Promising Treatment Approach in Pancreatic Cancer

“…Lee et al found that ablative RT is more effective than fractionated RT at recruiting T cells in a murine orthotopic pancreatic tumor model. Fractionated RT induced more myeloid-derived suppressor cell infiltration than ablative RT [47].…”