Fluorine-MRI Based Longitudinal Immuno-Microenvironment-Monitoring for Pancreatic Cancer.

BACKGROUND

Pancreatic cancer has a poor prognosis. Targeting Kirsten Rat Sarcoma (KRAS) mutation and its related pathways may enhance immunotherapy efficacy. While in vivo monitoring of therapeutic response and immune cell migration remains challenging, Fluorine-19 MRI (F MRI) may allow noninvasive longitudinal imaging of immune cells.

PURPOSE

Evaluating the potential of F MRI for monitoring changes in the tumor immune microenvironment, in response to combined SHP2/MEK inhibition.

STUDY TYPE

Pre-clinical animal study.

ANIMAL MODEL

Murine genetically engineered pancreatic cancer model (N = 20, both sexes).

FIELD STRENGTH/SEQUENCE: 9.4-T, two-dimensional multi-slice Rapid Acquisition with Relaxation Enhancement sequence. Intravenous injection of F-perfluorocarbon (PFC) nanoparticles.

ASSESSMENT

Upon tumor detection by conventional H MRI screening, F MRI was performed in mice 24 hours after PFC nanoparticle administration. Animals were randomly assigned to four treatment groups: allosteric Src-homology-2-containing protein tyrosine phosphatase 2 (SHP2) inhibitor SHP099, the mitogen-activated extracellular signal-regulated kinase 1/2 (MEK1/2) inhibitor Trametinib, the combination of both, or a vehicle control (4 to 6 mice each group), administered every other day per oral gavage. H and F MRI was repeated 7 days and 14 days later. Pancreatic immune cell infiltrates were analyzed by flow cytometry and multiplex immunohistofluorescence (mIHF) upon sacrifice.

STATISTICAL TESTS

Independent t-tests and one-way analysis of variance.

RESULTS

F MRI revealed continuous decrease of PFC-signals in tumors from vehicle controls (100%, 80%, and 74% on days 0, 7, and 14, respectively), contrasting with stable or increasing signals under KRAS-pathway-directed treatment. MEK inhibition showed 100%, 152%, and 84% and dual SHP2/MEK1/2 inhibition demonstrated signals of 100%, 134%, and 100% on days 0, 7, 14, respectively. mIHF analyses indicated CD11b macrophages/monocytes as primary contributors to the observed F MRI signal differences.

DATA CONCLUSION

F MRI might provide non-invasive longitudinal estimates for abundance and spatial distribution of CD11b macrophages/monocytes in pancreatic cancer.

EVIDENCE LEVEL

1 TECHNICAL EFFICACY: Stage 2.