Immune inactivation by APOBEC3B enrichment predicts response to chemotherapy and survival in gastric cancer

Xia, Siyu; Gu, Yun; Zhang, Haijian; Fei, Yuchao; Cao, Yifan; Fang, Hanji; Wang, Jieti; Lin, Chao; Zhang, Heng; He, Li; He, Hongyong; Xu, Jiejie; Li, Ruochen; Líu, Hao; Zhang, Weijuan

doi:10.1080/2162402x.2021.1975386

Cited by 17 publications

(18 citation statements)

References 46 publications

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“…When it comes to APOBEC3B, it is the most widely investigated member of APOBEC family and causes a variety of mutagenic outcomes 55 , but its biological impact on cancers still remains unclear, even contrary. For example, Xia and colleagues reported that APOBEC3B upregulation predicts immune inactivation and worse survival in gastric cancer 56 , while Serebrenik and colleagues reported that APOBEC3B is overexpressed in a subset of clear cell ovarian cancer and correlates with improved clinical outcomes 57 . As regards to cancer therapy, APOBEC3B promotes tamoxifen resistance in ER-positive breast cancer but predicts favorable response of ICB in NSCLC 14 , 15 .…”

Section: Discussionmentioning

confidence: 99%

APOBEC-mediated mutagenesis is a favorable predictor of prognosis and immunotherapy for bladder cancer patients: evidence from pan-cancer analysis and multiple databases

Shi

Wang

et al. 2022

Theranostics

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Background: The APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) family-mediated mutagenesis is widespread in human cancers. However, our knowledge of the biological feature and clinical relevance of APOBECs and APOBEC mutagenesis in cancers remains limited. Methods: In this study, with a series of bioinformatic and statistical approaches, we performed a comprehensive analysis of multiple levels of data, including whole-exome sequencing (WES) and targeted next-generation sequencing (NGS), transcriptome (bulk RNA-seq and single-cell RNA-seq), immune signatures and immune checkpoint blockade (ICB) potential, patient survival and drug sensitivity, to reveal the distribution characteristics and clinical significance of APOBECs and APOBEC mutagenesis in pan-cancer especially bladder cancer (BLCA). Results: APOBEC mutagenesis dominates in the mutational patterns of BLCA. A higher enrichment score of APOBEC mutagenesis correlates with favorable prognosis, immune activation and potential ICB response in BLCA patients. APOBEC3A and 3B play a significant role in the malignant progression and cell differentiation within the tumor microenvironment. Furthermore, using machine learning approaches, a prognostic APOBEC mutagenesis-related model was established and validated in different BLCA cohorts. Conclusions: Our study illustrates the characterization of APOBECs and APOBEC mutagenesis in multiple cancer types and highlights its potential value as a promising biomarker for prognosis and immunotherapy in BLCA.

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Section: Discussionmentioning

confidence: 99%

APOBEC-mediated mutagenesis is a favorable predictor of prognosis and immunotherapy for bladder cancer patients: evidence from pan-cancer analysis and multiple databases

Shi

Wang

et al. 2022

Theranostics

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“…access expression of APOBEC3B was associated with reduced CD8 T cell genes (CD8A, CD8B) and T cell effectors (IFNG, GZMH and GZMK) in ESCC patients, this result was consistent with the reports in hepatocellular carcinoma and gastric cancer. 19 48 3, 5-diiodotyrosine could significantly upregulated the expression of PD-L1 in tumor cells, which suggested that 3, 5-diiodotyrosine may be more effective in combination with inhibitors of immune checkpoint PD-L1.…”

Section: Discussionmentioning

confidence: 99%

Identification of natural product 3, 5-diiodotyrosine as APOBEC3B inhibitor to prevent somatic mutation accumulation and cancer progression

Chen

Sui

Ning

et al. 2022

J Immunother Cancer

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BackgroundThe development of cancer is largely dependent on the accumulation of somatic mutations, indicating the potential to develop cancer chemoprevention agents targeting mutation drivers. However, ideal cancer chemoprevention agents that can effectively inhibit the mutation drivers have not been identified yet.MethodsThe somatic mutation signatures and expression analyses of APOBEC3B were performed in patient with pan-cancer. The computer-aided screening and skeleton-based searching were performed to identify natural products that can inhibit the activity of APOBEC3B. 4-nitroquinoline-1-oxide (4-NQO)-induced spontaneous esophageal squamous cell carcinoma (ESCC) and azoxymethane/dextran sulfate sodium (AOM/DSS)-induced spontaneous colon cancer mouse models were conducted to investigate the influences of APOBEC3B inhibitor on the prevention of somatic mutation accumulation and cancer progression.ResultsHere, we discovered that the cytidine deaminase APOBEC3B correlated somatic mutations were widely observed in a variety of cancers, and its overexpression indicated poor survival. SMC247 (3, 5-diiodotyrosine), as a source of kelp iodine without side effects, could strongly bind APOBEC3B (KD=65 nM) and effectively inhibit its deaminase activity (IC50=1.69 µM). Interestingly, 3, 5-diiodotyrosine could significantly reduce the clusters of mutations, prevent the precancerous lesion progression, and prolong the survival in 4-NQO-induced spontaneous ESCC and AOM/DSS-induced spontaneous colon cancer mouse models. Furthermore, 3, 5-diiodotyrosine could reduce colitis, increase the proportion and function of T lymphocytes via IL-15 in tumor microenvironment. The synergistic cancer prevention effects were observed when 3, 5-diiodotyrosine combined with PD-1/PD-L1 blockade.ConclusionsThis is the first prove-of-concept study to elucidate that the natural product 3, 5-diiodotyrosine could prevent somatic mutation accumulation and cancer progression through inhibiting the enzymatic activity of APOBEC3B. In addition, 3, 5-diiodotyrosine could reduce the colitis and increase the infiltration and function of T lymphocytes via IL-15 in tumor microenvironment. 3, 5-diiodotyrosine combined with PD-1/PD-L1 blockade could elicit synergistic cancer prevention effects, indicating a novel strategy for both prevent the somatic mutation accumulation and the immune-suppressive microenvironment exacerbation.

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“…According to Xia et al, APOBEC3B is a potential biomarker for predicting response to immunotherapy and survival in gastric cancer patients. In particular, APOBEC3B high CD8+ T cell high gastric cancer patients were more likely to benefit from adjuvant chemotherapy (ACT) and PD-1 blockade [ 21 ]. Hot tumors tend to have a higher immune cell infiltration and immune checkpoint expression [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

APOBEC3B and CD274 as Combined Biomarkers for Predicting Response to Immunotherapy in Urothelial Carcinoma of the Bladder

Zhang

Cheng

Wang

et al. 2022

Journal of Oncology

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Immunotherapy has become a promising form of treatment for cancers. There is a need to predict response to immunotherapy accurately. In the UCSC Xena, pan-cancer analysis revealed a positive relationship between APOBEC3B (A3B) and tumor mutational burden ( R = 0.28 , P < 0.001 ) and microsatellite instability ( R = 0.12 , P < 0.05 ). Naturally, the A3B high expression group had higher tumor mutational burden and microsatellite instability than the low expression group. The bladder cancer (BLCA) cohort in The Cancer Genome Atlas (TCGA) revealed tumor mutational signatures of A3B high and low expression groups. Compared to the low expression group, the high expression group had a higher number of SNPs and mutations. Subsequently, A3B was profiled for immune cell infiltration and immune checkpoints in bladder cancer. The results showed that A3B was positively correlated with most immune cells. Compared with the A3B low expression group, the A3B high expression group had higher expression of immune checkpoints. A3B was positively correlated with CD274 ( R = 0.12 , P = 0.016 ). This indicated that the high expression of A3B may have a better response to immunotherapy. Furthermore, data from the IMvigor210 immunotherapy clinical trial was used to confirm the findings of this study. The combined survival analysis of A3B and CD274 showed that the group of patients with high expression of CD274 and A3B was found to have a significantly higher survival rate than the rest of the patient group ( P < 0.047 ). The results demonstrated that A3B has a significant role in immunotherapy. Moreover, the combined biomarkers of A3B and CD274 were more effective in predicting response to immunotherapy in bladder urothelial carcinoma. The findings of this study provide valuable insights for precision medicine.

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Immune inactivation by APOBEC3B enrichment predicts response to chemotherapy and survival in gastric cancer

Cited by 17 publications

References 46 publications

APOBEC-mediated mutagenesis is a favorable predictor of prognosis and immunotherapy for bladder cancer patients: evidence from pan-cancer analysis and multiple databases

APOBEC-mediated mutagenesis is a favorable predictor of prognosis and immunotherapy for bladder cancer patients: evidence from pan-cancer analysis and multiple databases

Identification of natural product 3, 5-diiodotyrosine as APOBEC3B inhibitor to prevent somatic mutation accumulation and cancer progression

APOBEC3B and CD274 as Combined Biomarkers for Predicting Response to Immunotherapy in Urothelial Carcinoma of the Bladder

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