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2024 ; 12
(7
): ä Nephropedia Template TP
gab.com Text
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English Wikipedia
Blockade of glucose-6-phosphate dehydrogenase induces immunogenic cell death and
accelerates immunotherapy
#MMPMID39089738
Nakamura M
; Magara T
; Yoshimitsu M
; Kano S
; Kato H
; Yokota K
; Okuda K
; Morita A
J Immunother Cancer
2024[Jul]; 12
(7
): ä PMID39089738
show ga
BACKGROUND: Enhanced glucose metabolism has been reported in many cancers.
Glucose-6-phosphate dehydrogenase (G6PD) is a rate-limiting enzyme involved in
the pentose phosphate pathway, which maintains NADPH levels and protects cells
from oxidative damage. We recently found that low G6PD expression correlates with
active tumor immunity. However, the mechanism involving G6PD and tumor immunity
remained unclear. METHODS: We conducted in vitro studies using G6PD-knocked down
malignant melanoma cells, pathway analysis using the GEO dataset, in vivo studies
in combination with immune checkpoint inhibitors (ICIs) using a mouse melanoma
model, and prognostic analysis in 42 melanoma patients and 30 lung cancer
patients who were treated with ICIs. RESULTS: Inhibition of G6PD, both chemically
and genetically, has been shown to decrease the production of NADPH and reduce
their oxidative stress tolerance. This leads to cell death, which is accompanied
by the release of high mobility group box 1 and the translocation of calreticulin
to the plasma membrane. These findings suggested that inhibiting G6PD can induce
immunogenic cell death. In experiments with C57BL/6 mice transplanted with
G6PD-knockdown B16 melanoma cells and treated with anti-PD-L1 antibody, a
significant reduction in tumor size was observed. Interestingly, inhibiting G6PD
in only a part of the lesions increased the sensitivity of other lesions to ICI.
Additionally, out of 42 melanoma patients and 30 lung cancer patients treated
with ICIs, those with low G6PD expression had a better prognosis than those with
high G6PD expression (p=0.0473; melanoma, p=0.0287; lung cancer). CONCLUSION:
G6PD inhibition is a potent therapeutic strategy that triggers immunogenic cell
death in tumors, significantly augmenting the efficacy of immunotherapies.
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