Immunotherapy targeting the PD-1/PD-L1 axis has shown promise in some cancer subtypes but has failed in many solid tumors, including pancreatic ductal adenocarcinoma (PDAC). This is largely attributed to the migration of immune cells into the characteristically desmoplastic stroma in PDAC, creating an immune-quiescent tumor microenvironment (TME). MYC is an oncogenic protein that orchestrates an immune-suppressive TME and has been linked to PD-L1. We hypothesize that MYC-targeted therapy will make tumors “hot” by activating the TME, increasing PD-L1 antigen presentation for therapeutic targeting. In order to test this hypothesis, we created a molecular imaging agent from an anti-PD-L1 antibody (clone 6E11, Genentech) to noninvasively assess effects of targeted therapy on PD-L1 antigen presentation in vivo. Anti-PD-L1 was conjugated to desferrioxamine to enable labeling with zirconium-89 (89Zr) for positron emission tomography (PET) imaging. KPC PDAC cells were inoculated orthotopically into the pancreas of C57BL/6J mice. KPC tumor-bearing mice were then treated with ERK inhibitor SCH772984 (90 mg/kg daily for 6 days) and injected with [89Zr]Zr-anti-PD-L1 to undergo serial PET imaging and biodistribution. Tumors were resected and stained for MYC and PD-L1 via immunofluorescence. The specific activity and molar activity for [89Zr]Zr-PD-L1 were 4 mCi/mg and 600 mCi/mmol, respectively, and radiochemical yield and purity was &gt;98%. We observed statistically significant increase in uptake of [89Zr]Zr-PD-L1 (P &lt; 0.05) upon treatment with ERK inhibitor, with a correlation to increased expression of PD-L1 via ex vivo immunofluorescence. In conclusion, we have shown a significant increase in the uptake of [89Zr]Zr-PD-L1 from indirect MYC-targeted therapy, correlated to an increased expression of PD-L1 ex vivo. Further studies to fully characterize the immune microenvironment via ex vivo flow cytometry and immunohistochemistry are underway to dissect the mechanism of this phenomenon. We anticipate our noninvasive [89Zr]Zr-PD-L1 tool will drive synergistic combinatorial therapeutic approaches in PDAC.

Altering the tumor microenvironment to improve immunotherapy: Molecular imaging of PD-L1 in pancreatic cancer

2019 Fall National Meeting

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