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Common germline variants of the human APOE gene modulate melanoma progression and survival
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Common germline variants of the human APOE gene modulate melanoma progression and survival
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Journal Article
Common germline variants of the human APOE gene modulate melanoma progression and survival
2020
Overview
Common germline variants of the
APOE
gene are major risk modifiers of neurodegenerative and atherosclerotic diseases
1
–
3
, but their effect on cancer outcome is poorly defined. Here we report that, in a reversal of their effect on Alzheimer’s disease, the
APOE4
and
APOE2
variants confer favorable and poor outcomes in melanoma, respectively. Mice expressing the human
APOE4
allele exhibited reduced melanoma progression and metastasis relative to
APOE2
mice.
APOE4
mice exhibited enhanced anti-tumor immune activation relative to
APOE2
mice, and T cell depletion experiments showed that the effect of
APOE
genotype on melanoma progression was mediated by altered anti-tumor immunity. Consistently, patients with melanoma carrying the
APOE4
variant experienced improved survival in comparison to carriers of
APOE2
. Notably,
APOE4
mice also showed improved outcomes under PD1 immune checkpoint blockade relative to
APOE2
mice, and patients carrying
APOE4
experienced improved anti-PD1 immunotherapy survival after progression on frontline regimens. Finally, enhancing
APOE
expression via pharmacologic activation of liver X receptors, previously shown to boost anti-tumor immunity
4
, exhibited therapeutic efficacy in
APOE4
mice but not in
APOE2
mice. These findings demonstrate that pre-existing hereditary genetics can impact progression and survival outcomes of a future malignancy and warrant prospective investigation of
APOE
genotype as a biomarker for melanoma outcome and therapeutic response.
Heritable
APOE
variants in patients with melanoma influence anti-tumor immunity and modulate metastatic progression and response to immunotherapy.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Animals
/ Apolipoprotein E2 - genetics
/ Apolipoprotein E3 - genetics
/ Apolipoprotein E4 - genetics
/ Biomedical and Life Sciences
/ Female
/ Genetics
/ Genotype
/ Germ-Line Mutation - genetics
/ Germ-Line Mutation - immunology
/ Humans
/ Immunity
/ Letter
/ Melanoma
/ Mice
/ Programmed Cell Death 1 Receptor - antagonists & inhibitors
/ Programmed Cell Death 1 Receptor - immunology
/ Survival
/ Tumors
