Anti PD-1 treatment increases [18F]FDG uptake by cancer cells in a mouse B16F10 melanoma model

Abstract

BackgroundProgrammed cell death 1 (PD-1) inhibitors act as immune checkpoint inhibitors and are more effective for improving survival time with less toxicity as compared with conventional chemotherapies. In anti PD-1 therapy, it is important to evaluate metabolism in the cancer microenvironment, as this helps to clarify the pathological conditions. Herein, we investigate the early effects of PD-1 therapy on 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) uptake in vivo, focusing on cell distribution and glycolysis in both cancer and immune cells.ResultsIn a B16F10 melanoma model, [18F]FDG-positron emission tomography (PET) was performed before treatment and 7 days after the start of treatment. Values were calculated as the percentage-injected activity per gram of tissue (%IA/g). Flow-cytometry was then performed to assess immune cell populations and glucose metabolism. There was a negligible difference in [18F]FDG uptake between tumors in the treatment group and non-treatment group before the treatment. In contrast, mean [18F]FDG uptake in the treatment group tumors was significantly higher (8.06 ± 0.48 %IA/g; P = 0.0074) than that in the non-treatment group (4.02 ± 1.03 %IA/g) after anti PD-1 treatment. Assessment of tumor immune cell populations showed that treatment slightly enriched CD8+ T cells and CD4+ T cells; however, infiltration of immune cells was negligible, and thus, immune cells were not responsible for the increase in [18F]FDG uptake. On the other hand, anti PD-1 treatment significantly increased glucose transporter 1 (GLUT1) and hexokinase II expression in CD45− cancer cells, indicating that anti PD-1 treatment increased glucose metabolism in cancer cells.ConclusionThe present study shows that anti PD-1 therapy increases glucose metabolism in cancer cells.Electronic supplementary materialThe online version of this article (10.1186/s13550-018-0433-1) contains supplementary material, which is available to authorized users.

Influence on [18F]FDG uptake by cancer cells after anti-PD-1 therapy in an enforced-immune activated mouse tumor

“…Anti-PD-1 antibody (250 μg) was administrated twice intra-peritoneally (i.p.) 5 days apart according to the previous methods [11,16,17]. On days 0 and 5, tumors were injected with 10 μg of 3′3′-cGAMP (Invivogen, San Diego, CA) complexed with 3 μL of Lipofectamine 2000 (Invivogen) was injected into the tumor [15].…”

“…In this study, tumor volumes were measured in mice and used for PET study or flow-cytometry analysis. To compare the cGAMP-injected B16F10 model with the B16F10 model, data of the non-treatment group and anti-PD-1 treated group were quoted from the previous report [11].…”

“…Thirteen mice were used for PET, ex vivo gamma counting, autoradiography, and staining (cGAMP alone group n = 6, cGAMP/anti-PD-1 combination group n = 7). The PET study was performed as described in our previous manuscript [11]. Briefly, [ 18 F]FDG (3.5 MBq) in 100 μL of saline was administrated to C57/BL6 mice via a lateral tail vein and [ 18 F]FDG-PET/CT images were acquired on an Inveon small-animal multimodality PET/CT system (Siemens Medical Solutions, Knoxville, TN).…”

“…TLG was defined as the product of MTV and mean 30% . Previous data quoted from [11] was reanalyzed to measure the mean 30% and TLG.…”

“…It is important to clarify the effect of anti-PD-1 treatment on 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) uptake to evaluate the value of [ 18 F]FDG for monitoring the effects of anti-PD-1 therapies. We previously reported that anti-PD-1 treatment affected tumor glycolysis by using [ 18 F]FDG positron emission tomography (PET) [11]. That study showed that anti-PD-1 therapy in a mouse B16F10 melanoma model increased glucose metabolism in cancer cells at the point where anti-PD-1 therapy did not cause significant inhibition of tumor growth.…”