ALKBH5 regulates anti-PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment

Na Li; Yuqi Kang; Lingling Wang; Sarah Huff; Rachel Tang; Hui Hui; Kriti Agrawal; Gwendolyn Michelle Gonzalez; Yinsheng Wang; Sandip Pravin Patel; Tariq M Rana

doi:10.1073/pnas.1918986117

ALKBH5 regulates anti-PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment

Proc Natl Acad Sci U S A. 2020 Aug 18;117(33):20159-20170. doi: 10.1073/pnas.1918986117. Epub 2020 Aug 3.

Authors

Na Li¹, Yuqi Kang^{1

2}, Lingling Wang¹, Sarah Huff¹, Rachel Tang¹, Hui Hui^{1

2}, Kriti Agrawal^{1

2}, Gwendolyn Michelle Gonzalez^{3

4}, Yinsheng Wang^{3

4}, Sandip Pravin Patel⁵, Tariq M Rana^{6

5}

Affiliations

¹ Division of Genetics, Department of Pediatrics, Program in Immunology, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093.
² Bioinformatics Program, University of California San Diego, La Jolla, CA 92093.
³ Environmental Toxicology Graduate Program, University of California, Riverside, CA 92521.
⁴ Department of Chemistry, University of California, Riverside, CA 92521.
⁵ San Diego Center for Precision Immunotherapy, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093.
⁶ Division of Genetics, Department of Pediatrics, Program in Immunology, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093; [email protected].

Abstract

Although immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, many patients do not respond or develop resistance to ICB. N⁶ -methylation of adenosine (m⁶A) in RNA regulates many pathophysiological processes. Here, we show that deletion of the m⁶A demethylase Alkbh5 sensitized tumors to cancer immunotherapy. Alkbh5 has effects on m⁶A density and splicing events in tumors during ICB. Alkbh5 modulates Mct4/Slc16a3 expression and lactate content of the tumor microenvironment and the composition of tumor-infiltrating Treg and myeloid-derived suppressor cells. Importantly, a small-molecule Alkbh5 inhibitor enhanced the efficacy of cancer immunotherapy. Notably, the ALKBH5 gene mutation and expression status of melanoma patients correlate with their response to immunotherapy. Our results suggest that m⁶A demethylases in tumor cells contribute to the efficacy of immunotherapy and identify ALKBH5 as a potential therapeutic target to enhance immunotherapy outcome in melanoma, colorectal, and potentially other cancers.

Keywords: GVAX; PD-1 blockade; immunotherapy enhancers; m6A RNA modification; melanoma.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

AlkB Homolog 5, RNA Demethylase / genetics
AlkB Homolog 5, RNA Demethylase / metabolism*
Antibodies
Cancer Vaccines / immunology*
Cytokines / genetics
Cytokines / metabolism
Gene Deletion
Gene Expression Regulation, Neoplastic
Humans
Lactates / metabolism*
Melanoma / metabolism*
Melanoma / therapy
Methyltransferases / genetics
Methyltransferases / metabolism
Monocarboxylic Acid Transporters / genetics
Monocarboxylic Acid Transporters / metabolism
Muscle Proteins / genetics
Muscle Proteins / metabolism
Myeloid-Derived Suppressor Cells / physiology
Programmed Cell Death 1 Receptor / immunology*
RNA Splice Sites
RNA Splicing
Symporters / genetics
Symporters / metabolism
T-Lymphocytes, Regulatory / physiology*
Transcriptome
Tumor Microenvironment
Vascular Endothelial Growth Factor A / genetics
Vascular Endothelial Growth Factor A / metabolism

Substances

Antibodies
Cancer Vaccines
Cytokines
GVAX vaccine
Lactates
Monocarboxylic Acid Transporters
Muscle Proteins
PDCD1 protein, human
Programmed Cell Death 1 Receptor
RNA Splice Sites
SLC16A3 protein, human
SLC16A4 protein, human
Symporters
Vascular Endothelial Growth Factor A
ALKBH5 protein, human
AlkB Homolog 5, RNA Demethylase
Methyltransferases
METTL3 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding