Metabolic predictors of response to immune checkpoint blockade therapy

Shorer, Ofir; Yizhak, Keren

doi:10.1016/j.isci.2023.108188

Cited by 4 publications

(1 citation statement)

References 83 publications

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“…8c-d, Supplementary Table 8 ). Of note, NADPH can be generated from NAD + via phosphorylation by NAD + kinase to NADP + and subsequent reduction of NADP + to NADPH by glucose-6-phosphate dehydrogenase (G6PD), an enzyme also enriched in exhausted CD8 + T cells in melanoma 33 . Further metabolomic analysis of CD38i-treated, chronically TCR-stimulated B7-H3.CAR-T cells demonstrated increased levels of both NAD + and NADP ( Fig.…”

Section: Disrupting Cd38 Restores Nad+ In Exhausted T Cellsmentioning

confidence: 99%

Disrupting CD38-driven T cell dysfunction restores sensitivity to cancer immunotherapy

Revach,

Cicerchia,

Shorer

et al. 2024

Preprint

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A central problem in cancer immunotherapy with immune checkpoint blockade (ICB) is the development of resistance, which affects 50% of patients with metastatic melanoma. T cell exhaustion, resulting from chronic antigen exposure in the tumour microenvironment, is a major driver of ICB resistance. Here, we show that CD38, an ecto-enzyme involved in nicotinamide adenine dinucleotide (NAD+) catabolism, is highly expressed in exhausted CD8+ T cells in melanoma and is associated with ICB resistance. Tumour-derived CD38hiCD8+ T cells are dysfunctional, characterised by impaired proliferative capacity, effector function, and dysregulated mitochondrial bioenergetics. Genetic and pharmacological blockade of CD38 in murine and patient-derived organotypic tumour models (MDOTS/PDOTS) enhanced tumour immunity and overcame ICB resistance. Mechanistically, disrupting CD38 activity in T cells restored cellular NAD+ pools, improved mitochondrial function, increased proliferation, augmented effector function, and restored ICB sensitivity. Taken together, these data demonstrate a role for the CD38-NAD+ axis in promoting T cell exhaustion and ICB resistance, and establish the efficacy of CD38 directed therapeutic strategies to overcome ICB resistance using clinically relevant, patient-derived 3D tumour models.

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Section: Disrupting Cd38 Restores Nad+ In Exhausted T Cellsmentioning

confidence: 99%

Disrupting CD38-driven T cell dysfunction restores sensitivity to cancer immunotherapy

Revach,

Cicerchia,

Shorer

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

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Unlocking potential: the role of the electron transport chain in immunometabolism

Zotta,

O’Neill,

Yin

2024

Trends in Immunology

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Single-cell meta-analysis of T cells reveals clonal dynamics of response to checkpoint immunotherapy

Shorer,

Pinhasi,

Yizhak

2024

Preprint

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Despite the crucial role of T cell clones in the anti-tumor activity, their characterization and association with clinical outcome following immune checkpoint inhibitors (ICI) is lacking. Here we analyzed paired single-cell RNA-sequencing/T-cell receptor sequencing of 767,606 T cells from 460 samples spanning 6 cancer types. We found a robust signature of response based on expanded CD8+> clones that differentiates between responders and non-responders. Analysis of persistent clones showed transcriptional changes that are differentially induced by therapy in the different response groups, suggesting an improved reinvigoration capacity in responding patients. Moreover, a gene trajectory analysis revealed changes in the pseudo-temporal state of de-novo clones that are associated with response to therapy. Lastly, we found that clones shared between tumor and blood are more abundant in non-responders and execute distinct transcriptional programs. Overall, our results highlight differences in clonal transcriptional states that are linked to patient response, offering valuable insights into the mechanisms driving effective anti-tumor immunity.

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Metabolic predictors of response to immune checkpoint blockade therapy

Cited by 4 publications

References 83 publications

Disrupting CD38-driven T cell dysfunction restores sensitivity to cancer immunotherapy

Disrupting CD38-driven T cell dysfunction restores sensitivity to cancer immunotherapy

Unlocking potential: the role of the electron transport chain in immunometabolism

Single-cell meta-analysis of T cells reveals clonal dynamics of response to checkpoint immunotherapy

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