Dataset Information

Hyperpolarized ¹³C-Pyruvate to Assess Response to Anti-PD1 Immune Checkpoint Inhibition in YUMMER 1.7 Melanoma Xenografts.

ABSTRACT: There is currently no consensus to determine which advanced melanoma patients will benefit from immunotherapy, highlighting the critical need to identify early-response biomarkers to immune checkpoint inhibitors. The aim of this work was to evaluate in vivo metabolic spectroscopy using hyperpolarized (HP) ¹³C-pyruvate and ¹³C-glucose to assess early response to anti-PD1 therapy in the YUMMER1.7 syngeneic melanoma model. The xenografts showed a significant tumor growth delay when treated with two cycles of an anti-PD1 antibody compared to an isotype control antibody. ¹³C-MRS was performed in vivo after the injection of hyperpolarized ¹³C-pyruvate, at baseline and after one cycle of immunotherapy, to evaluate early dynamic changes in ¹³C-pyruvate-¹³C-lactate exchange. Furthermore, ex vivo ¹³C-MRS metabolic tracing experiments were performed after U-¹³C-glucose injection following one cycle of immunotherapy. A significant decrease in the ratio of HP ¹³C-lactate to ¹³C-pyruvate was observed in vivo in comparison with the isotype control group, while there was a lack of change in the levels of ¹³C lactate and ¹³C alanine issued from ¹³C glucose infusion, following ex vivo assessment on resected tumors. Thus, these results suggest that hyperpolarized ¹³C-pyruvate could be used to assess early response to immune checkpoint inhibitors in melanoma patients.

SUBMITTER: Farah C

PROVIDER: S-EPMC9917169 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Publications

Hyperpolarized 13C-Pyruvate to Assess Response to Anti-PD1 Immune Checkpoint Inhibition in YUMMER 1.7 Melanoma Xenografts.

Farah Chantale C Neveu Marie-Aline MA Bouzin Caroline C Knezevic Zorica Z Gallez Bernard B Leucci Eleonora E Baurain Jean-François JF Mignion Lionel L Jordan Bénédicte F BF

International journal of molecular sciences 20230128 3

There is currently no consensus to determine which advanced melanoma patients will benefit from immunotherapy, highlighting the critical need to identify early-response biomarkers to immune checkpoint inhibitors. The aim of this work was to evaluate in vivo metabolic spectroscopy using hyperpolarized (HP) 13C-pyruvate and 13C-glucose to assess early response to anti-PD1 therapy in the YUMMER1.7 syngeneic melanoma model. The xenografts showed a significant tumor growth delay ...[more]

PMID: 36768822

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Project description:The detection and treatment monitoring of inflammatory states remain challenging in part due to the multifactorial mechanisms of immune activation and spectrum of clinical manifestations. Currently, diagnostic strategies tend to be subjective and limited quantitative tools exist to monitor optimal treatment strategies. Pro-inflammatory M1 polarized macrophages exhibit a distinct metabolic glycolytic phenotype compared to the continuum of M2 polarization states. In the present study, the distinct metabolic phenotypes of resting and activated macrophages were successfully characterized and quantified using hyperpolarized carbon-13 (13C) labeled pyruvate and its metabolic products, i.e. lactate, as a biomarker of resting, disease and treated states. Methods: Mouse macrophage J774A.1 cells were used as a model system in an NMR compatible bioreactor to facilitate dynamic hyperpolarized 13C measurements. The glycolytic metabolism of the cells in the quiescent or resting state were compared with macrophages stimulated by lipopolysaccharide, a classical M1 activator using hyperpolarized 13C labeled pyruvate. Additionally, the activated macrophages were also treated with a non-steroidal anti-inflammatory drug to assess the changes in hyperpolarized lactate signal. The hyperpolarized lactate signals were then correlated using biochemical and molecular assays. Results: We first validated our model system of inflammatory cells by the hallmarks of M1 polarization using steady state metabolic profiling with high resolution NMR in conjunction with nitric oxide Greiss assay, enzyme activity, and mRNA expression. Subsequently, we clearly showed that the cutting edge technology of hyperpolarized 13C NMR can be used to detect elevated lactate levels in M1 polarized macrophages in comparison to control and non-steroidal anti-inflammatory drug treated M2 states. Conclusion: Hyperpolarized 13C lactate has the potential to serve as a biomarker to non-invasively detect and quantify pro-inflammatory state of immune regulatory cells and its response to therapy.

Dataset Information

Hyperpolarized ¹³C-Pyruvate to Assess Response to Anti-PD1 Immune Checkpoint Inhibition in YUMMER 1.7 Melanoma Xenografts.

Publications

Hyperpolarized <sup>13</sup>C-Pyruvate to Assess Response to Anti-PD1 Immune Checkpoint Inhibition in YUMMER 1.7 Melanoma Xenografts.

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