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

Mayu Tomita; Motofumi Suzuki; Yusuke Kono; Kohei Nakajima; Takuma Matsuda; Yuji Kuge; Mikako Ogawa

doi:10.1186/s13550-020-0608-4

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

EJNMMI Res. 2020 Mar 19;10(1):24. doi: 10.1186/s13550-020-0608-4.

Authors

Mayu Tomita¹, Motofumi Suzuki¹, Yusuke Kono¹, Kohei Nakajima¹, Takuma Matsuda¹, Yuji Kuge², Mikako Ogawa³

Affiliations

¹ Laboratory of Bioanalysis and Molecular Imaging, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, 060-0812, Japan.
² Central Institute of Isotope Science, Hokkaido University, Sapporo, Hokkaido, 060-0815, Japan.
³ Laboratory of Bioanalysis and Molecular Imaging, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, 060-0812, Japan. mogawa@pharm.hokudai.ac.jp.

Abstract

Background: Anti-programmed cell death 1 (PD-1) antibody is an immune checkpoint inhibitor, and anti-PD-1 therapy improves the anti-tumor functions of T cells and affects tumor microenvironment. We previously reported that anti-PD-1 treatment affected tumor glycolysis by using 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) positron emission tomography (PET). 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 a significant inhibition of tumor growth. However, the B16F10 melanoma model is poorly immunogenic, so it is not clear how anti-PD-1 treatment affects glucose metabolism in highly immunogenic cancer models. In this study, we used a cyclic dinucleotide GMP-AMP (cGAMP)-injected B16F10 melanoma model to investigate the effect of anti-PD-1 therapy on [¹⁸F]FDG uptake in a highly immune activated tumor in mice.

Results: To compare the cGAMP-injected B16F10 model with the B16F10 model, experiments were performed as described in our previous manuscript. [¹⁸F]FDG-PET was measured before treatment and 7 days after the start of treatment. In this study, [¹⁸F]FDG uptake in tumors in the cGAMP/anti-PD-1 combination group was lower than that in the anti-PD-1 treatment group tumors on day 7, as shown by PET and ex vivo validation. Flow-cytometry was performed to assess immune cell populations and glucose metabolism. Anti-PD-1 and/or cGAMP treatment increased the infiltration level of immune cells into tumors. The cGAMP/anti-PD-1 combination group had significantly lower levels of GLUT1^high cells/hexokinase II^high cells in CD45^- cancer cells compared with tumors in the anti-PD-1 treated group. These results suggested that if immune responses in tumors are higher than a certain level, glucose uptake in cancer cells is reduced depending on that level. Such a change of glucose uptake might be caused by the difference in infiltration or activation level of immune cells between the anti-PD-1 treated group and the cGAMP/anti-PD-1 combination group.

Conclusions: [¹⁸F]FDG uptake in cancer cells after anti-PD-1 treatment might be affected by the tumor immune microenvironment including immune cell infiltration, composition, and activation status.

Keywords: Immune checkpoint inhibitor; PD-1; [18F]FDG; cGAMP.