Identification of immunotherapy biomarkers for improving the clinical outcome of homologous recombination deficiency patients with lung adenocarcinoma

Homologous recombination deficiency (HRD) is a common molecular signature of genomic instability and has been shown to be a biomarker for targeted therapies. However, there is a lack of studies on the role of HRD changes in lung adenocarcinoma (LUAD) transcriptomics. HRD scores were determined using single nucleotide polymorphism (SNP) array data from LUAD patients from The Cancer Genome Atlas (TCGA) database. Transcriptional data from patients with different scores were analyzed to identify biomarkers associated with HRD. Candidate biomarkers were validated using Gene Expression Omnibus (GEO)-sourced datasets and an immunotherapy cohort. According to the bulk transcriptome and clinical characteristics of 912 LUAD patients and Single-cell RNA-seq of 9 LUAD patients from TCGA and GEO databases, we observed increased MS4A6A expression in HRD tumors; high MS4A6A expression predicted improved survival outcomes. Furthermore, a comprehensive analysis of the tumor immune microenvironment (TIME) revealed a positive correlation between MS4A6A expression and neoantigen loading and immune cell infiltration. Additionally, the immunotherapy cohort confirmed the possibility of using MS4A6A as a biomarker. Collectively, we suggest that MS4A6A is associated with HRD and provide a new perspective toward identifying promising biomarkers for immunotherapy.

[1]  Tao Jiang,et al.  Delineating the dynamic evolution from preneoplasia to invasive lung adenocarcinoma by integrating single-cell RNA sequencing and spatial transcriptomics , 2022, Experimental & Molecular Medicine.

[2]  N. Girard,et al.  Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. , 2022, The New England journal of medicine.

[3]  S. Jalal,et al.  Immunotherapy in Lung Cancer: Current Landscape and Future Directions , 2022, Frontiers in Immunology.

[4]  Yu Yao,et al.  Integration of Single-Cell RNA Sequencing and Bulk RNA Sequencing Data to Establish and Validate a Prognostic Model for Patients With Lung Adenocarcinoma , 2022, Frontiers in Genetics.

[5]  D. Schadendorf,et al.  Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. , 2022, The New England journal of medicine.

[6]  A. Jemal,et al.  Cancer statistics, 2022 , 2022, CA: a cancer journal for clinicians.

[7]  Yibo Gao,et al.  Comprehensive Analysis Uncovers Prognostic and Immunogenic Characteristics of Cellular Senescence for Lung Adenocarcinoma , 2021, Frontiers in Cell and Developmental Biology.

[8]  P. Fasching,et al.  Association of RAD51 with Homologous Recombination Deficiency (HRD) and clinical outcomes in untreated triple-negative breast cancer (TNBC): analysis of the GeparSixto randomized clinical trial. , 2021, Annals of oncology : official journal of the European Society for Medical Oncology.

[9]  A. Mantovani,et al.  The tetraspan MS4A family in homeostasis, immunity, and disease. , 2021, Trends in immunology.

[10]  P. Matthews,et al.  Diverse human astrocyte and microglial transcriptional responses to Alzheimer’s pathology , 2021, bioRxiv.

[11]  I. Ray-Coquard,et al.  PARP-inhibitors in epithelial ovarian cancer: Actual positioning and future expectations. , 2021, Cancer treatment reviews.

[12]  Anastasia G. Efthymiou,et al.  Integration of Alzheimer’s disease genetics and myeloid genomics identifies disease risk regulatory elements and genes , 2021, Nature Communications.

[13]  N. Ajami,et al.  Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial , 2021, Nature Medicine.

[14]  S. Shah,et al.  ESMO recommendations on predictive biomarker testing for homologous recombination deficiency and PARP inhibitor benefit in ovarian cancer. , 2020, Annals of oncology : official journal of the European Society for Medical Oncology.

[15]  Young-Joon Kim,et al.  Genome-wide identification of differentially methylated promoters and enhancers associated with response to anti-PD-1 therapy in non-small cell lung cancer , 2020, Experimental & Molecular Medicine.

[16]  Erin L. Schenk,et al.  Therapy-Induced Evolution of Human Lung Cancer Revealed by Single-Cell RNA Sequencing , 2020, Cell.

[17]  C. Sautès-Fridman,et al.  The Tumor Microenvironment in the Response to Immune Checkpoint Blockade Therapies , 2020, Frontiers in Immunology.

[18]  D. Lipson,et al.  Homologous recombination in lung cancer, germline and somatic mutations, clinical and phenotype characterization. , 2019, Lung cancer.

[19]  Baosheng Li,et al.  Pembrolizumab for the treatment of nonsmall cell lung cancer: Current status and future directions , 2019, Journal of cancer research and therapeutics.

[20]  K. Syrigos,et al.  Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. , 2019, The New England journal of medicine.

[21]  Jianying Zhou,et al.  Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial , 2019, The Lancet.

[22]  J. Wolchok,et al.  Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001 , 2019, Annals of oncology : official journal of the European Society for Medical Oncology.

[23]  A. Butte,et al.  Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage , 2018, Nature Immunology.

[24]  J. Lunceford,et al.  Pan-tumor genomic biomarkers for PD-1 checkpoint blockade–based immunotherapy , 2018, Science.

[25]  X. Liu,et al.  Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response , 2018, Nature Medicine.

[26]  D. Schadendorf,et al.  Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma , 2018, The New England journal of medicine.

[27]  Michael T. Zimmermann,et al.  Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas , 2018, Cell reports.

[28]  Steven J. M. Jones,et al.  The Immune Landscape of Cancer , 2018, Immunity.

[29]  J. Shih,et al.  Management of acquired resistance to EGFR TKI–targeted therapy in advanced non-small cell lung cancer , 2018, Molecular Cancer.

[30]  R. Bourgon,et al.  TGF-β attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells , 2018, Nature.

[31]  Matthew Slattery,et al.  A hypermorphic antioxidant response element is associated with increased MS4A6A expression and Alzheimer's disease , 2017, Redox biology.

[32]  R. Bourgon,et al.  Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial , 2017, The Lancet.

[33]  Y. Shentu,et al.  Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. , 2016, The New England journal of medicine.

[34]  Ignace Vergote,et al.  Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. , 2016, The New England journal of medicine.

[35]  Y. Drew,et al.  Homologous recombination deficiency and ovarian cancer. , 2016, European journal of cancer.

[36]  Pornpimol Charoentong,et al.  Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade , 2016, bioRxiv.

[37]  A Mayakonda,et al.  Maftools: Efficient analysis, visualization and summarization of MAF files from large-scale cohort based cancer studies , 2016, bioRxiv.

[38]  Z. Szallasi,et al.  Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer , 2016, Clinical Cancer Research.

[39]  L. Crinò,et al.  Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. , 2015, The New England journal of medicine.

[40]  J. Lunceford,et al.  Pembrolizumab for the treatment of non-small-cell lung cancer. , 2015, The New England journal of medicine.

[41]  Evan Z. Macosko,et al.  Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets , 2015, Cell.

[42]  W. Huber,et al.  Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 , 2014, Genome Biology.

[43]  G. Getz,et al.  Inferring tumour purity and stromal and immune cell admixture from expression data , 2013, Nature Communications.

[44]  Elisabeth Brambilla,et al.  Ectopic Activation of Germline and Placental Genes Identifies Aggressive Metastasis-Prone Lung Cancers , 2013, Science Translational Medicine.

[45]  A. Vincent-Salomon,et al.  Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. , 2012, Cancer research.

[46]  G. Mills,et al.  Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer , 2012, British Journal of Cancer.

[47]  Mats Lambe,et al.  Biomarker Discovery in Non–Small Cell Lung Cancer: Integrating Gene Expression Profiling, Meta-analysis, and Tissue Microarray Validation , 2012, Clinical Cancer Research.

[48]  Guangchuang Yu,et al.  clusterProfiler: an R package for comparing biological themes among gene clusters. , 2012, Omics : a journal of integrative biology.

[49]  Z. Szallasi,et al.  Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents. , 2012, Cancer discovery.

[50]  Takayuki Kosaka,et al.  Expression profile-defined classification of lung adenocarcinoma shows close relationship with underlying major genetic changes and clinicopathologic behaviors. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[51]  Satoru Miyano,et al.  Identification of genes upregulated in ALK-positive and EGFR/KRAS/ALK-negative lung adenocarcinomas. , 2012, Cancer research.

[52]  R. Tibshirani.  Regression Shrinkage and Selection via the Lasso , 1996 .