ALKBH5 regulates anti–PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment
| Autor: | Kriti Agrawal, Yuqi Kang, Yinsheng Wang, Sandip Pravin Patel, Hui Hui, Lingling Wang, Gwendolyn Gonzalez, Tariq M. Rana, Rachel Tang, Na Li, Sarah Huff |
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| Rok vydání: | 2020 |
| Předmět: |
Vascular Endothelial Growth Factor A
Medical Sciences T-Lymphocytes medicine.medical_treatment Programmed Cell Death 1 Receptor PD-1 blockade Muscle Proteins Gene mutation T-Lymphocytes Regulatory Cancer immunotherapy Tumor Microenvironment immunotherapy enhancers Cancer Multidisciplinary Symporters Melanoma AlkB Homolog 5 RNA Demethylase Biological Sciences Regulatory GVAX Gene Expression Regulation Neoplastic RNA Demethylase 5.1 Pharmaceuticals Lactates Cytokines Development of treatments and therapeutic interventions Monocarboxylic Acid Transporters RNA Splicing Cancer Vaccines Antibodies Vaccine Related Rare Diseases Immune system Genetics melanoma medicine Humans AlkB Homolog 5 Neoplastic Tumor microenvironment business.industry Myeloid-Derived Suppressor Cells Methyltransferases Immunotherapy medicine.disease Immune checkpoint Gene Expression Regulation Cancer research m(6)A RNA modification Immunization m6A RNA modification RNA Splice Sites Digestive Diseases Transcriptome business Gene Deletion |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, vol 117, iss 33 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1918986117 |
| Popis: | Significance N6-methylation of adenosine (m6A) RNA modification plays important roles in development and tumorigenesis. The functions and mechanisms of m6A demethylases during cancer immunotherapy is still unclear. Here we employed melanoma and colon syngeneic mouse models to study the roles of m6A demethylases ALKBH5 and FTO during anti–PD-1 antibody and GVAX vaccination therapy. We found that ALKBH5 knockout in tumor cells enhances efficacy of immunotherapy and prolonged mouse survival. ALKBH5 modulates target gene expression and gene splicing, leading to changes of metabolite contents, such as lactate in tumor microenvironment, which regulates suppressive lymphocytes Treg and myeloid-derived suppressor cell accumulations. Importantly, by using ALKBH5-specific inhibitor, we observed the similar phenotype, indicating future translational application of our findings. 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. |
| Databáze: | OpenAIRE |
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