Integrated Clinical, Molecular and Immunological Characterization of Pulmonary Sarcomatoid Carcinomas Reveals an Immune Escape Mechanism That May Influence Therapeutic Strategies

Pulmonary sarcomatoid carcinoma (PSC) has highly aggressive biological behaviour and poor clinical outcomes, raising expectations for new therapeutic strategies. We characterized 179 PSC by immunohistochemistry, next-generation sequencing and in silico analysis using a deep learning algorithm with respect to clinical, immunological and molecular features. PSC was more common in men, older ages and smokers. Surgery was an independent factor (p < 0.01) of overall survival (OS). PD-L1 expression was detected in 82.1% of all patients. PSC patients displaying altered epitopes due to processing mutations showed another PD-L1-independent immune escape mechanism, which also significantly influenced OS (p < 0.02). The effect was also maintained when only advanced tumour stages were considered (p < 0.01). These patients also showed improved survival with a significant correlation for immunotherapy (p < 0.05) when few or no processing mutations were detected, although this should be interpreted with caution due to the small number of patients studied. Genomic alterations for which there are already approved drugs were present in 35.4% of patients. Met exon 14 skipping was found more frequently (13.7%) and EGFR mutations less frequently (1.7%) than in other NSCLC. In summary, in addition to the divergent genomic landscape of PSC, the specific immunological features of this prognostically poor subtype should be considered in therapy stratification.

[1]  P. Kaumaya,et al.  A newly discovered PD-L1 B-cell epitope peptide vaccine (PDL1-Vaxx) exhibits potent immune responses and effective anti-tumor immunity in multiple syngeneic mice models and (synergizes) in combination with a dual HER-2 B-cell vaccine (B-Vaxx) , 2022, Oncoimmunology.

[2]  T. Blum,et al.  Landscape of Genomic Alterations and PD-L1 Expression in Early-Stage Non-Small-Cell Lung Cancer (NSCLC)—A Single Center, Retrospective Observational Study , 2022, International journal of molecular sciences.

[3]  P. Kaumaya,et al.  Preclinical Studies of a Novel Human PD-1 B-Cell Peptide Cancer Vaccine PD1-Vaxx From BALB/c Mice to Beagle Dogs and to Non-Human Primates (Cynomolgus Monkeys) , 2022, Frontiers in Oncology.

[4]  Gregory Riely,et al.  Management of Patients With Resectable and Metastatic Non–Small Cell Lung Cancer , 2022, The Journal of the National Comprehensive Cancer Network.

[5]  Yibo Gao,et al.  Multimodality Treatment of Pulmonary Sarcomatoid Carcinoma: A Review of Current State of Art , 2022, Journal of oncology.

[6]  B. Hadaschik,et al.  Proteasomal Processing Immune Escape Mechanisms in Platinum-Treated Advanced Bladder Cancer , 2022, Genes.

[7]  M. Schuler,et al.  Digital gene expression analysis of NSCLC-patients reveals strong immune pressure, resulting in an immune escape under immunotherapy , 2022, BMC cancer.

[8]  A. Toker,et al.  Clinicopathological and Prognostic Features of 67 Cases with Pulmonary Sarcomatoid Carcinoma: An 18-Year Single-Centre Experience , 2021, Oncology Research and Treatment.

[9]  F. D. De Braud,et al.  Immune-Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer With Uncommon Histology. , 2021, Clinical lung cancer.

[10]  Ying Cheng,et al.  Once-daily savolitinib in Chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: a multicentre, single-arm, open-label, phase 2 study. , 2021, The Lancet. Respiratory medicine.

[11]  H. Atreya,et al.  PD-1 derived CA-170 is an oral immune checkpoint inhibitor that exhibits preclinical anti-tumor efficacy , 2021, Communications biology.

[12]  Jianguo Sun,et al.  Survival Analysis and Prediction Model for Pulmonary Sarcomatoid Carcinoma Based on SEER Database , 2021, Frontiers in Oncology.

[13]  B. Seliger,et al.  Immune Therapy Resistance and Immune Escape of Tumors , 2021, Cancers.

[14]  Y. Huang,et al.  The genomic and immunologic profiles of pure pulmonary sarcomatoid carcinoma in Chinese patients. , 2021, Lung cancer.

[15]  Lujun Zhao,et al.  Clinicopathological characteristics and prognostic factors of pulmonary sarcomatoid carcinoma: a large population analysis , 2021, Annals of translational medicine.

[16]  Yibo Gao,et al.  Integrated molecular characterization reveals potential therapeutic strategies for pulmonary sarcomatoid carcinoma , 2020, Nature Communications.

[17]  E. Longchampt,et al.  Durable responses to immunotherapy of non-small cell lung cancers harboring MET exon-14-skipping mutation: A series of 6 cases. , 2020, Lung cancer.

[18]  H. Groen,et al.  Capmatinib in MET Exon 14-Mutated or MET-Amplified Non-Small-Cell Lung Cancer. , 2020, The New England journal of medicine.

[19]  T. Blum,et al.  A Novel Epitope Quality-Based Immune Escape Mechanism Reveals Patient’s Suitability for Immune Checkpoint Inhibition , 2020, Cancer management and research.

[20]  B. Seliger,et al.  Targeting the coding sequence: opposing roles in regulating classical and non-classical MHC class I molecules by miR-16 and miR-744 , 2020, Journal for immunotherapy of cancer.

[21]  G. Jiang,et al.  Pulmonary Sarcomatoid Carcinoma: Experience from SEER Database and Shanghai Pulmonary Hospital. , 2020, The Annals of thoracic surgery.

[22]  M. Garassino,et al.  Relationship Between Programmed Death Receptor-Ligand 1 Expression and Response to Checkpoint Inhibitor Immunotherapy in Pulmonary Sarcomatoid Carcinoma: A Pooled Analysis. , 2020, Clinical lung cancer.

[23]  O. Molinier,et al.  Efficacy of Immune Checkpoint Inhibitors in Lung Sarcomatoid Carcinoma. , 2020, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[24]  J. Galon,et al.  Tumor Immunology and Tumor Evolution: Intertwined Histories. , 2020, Immunity.

[25]  B. Seliger,et al.  Identification of miR-200a-5p targeting the peptide transporter TAP1 and its association with the clinical outcome of melanoma patients , 2020, Oncoimmunology.

[26]  G. Rossi,et al.  Approaches to Tumor Classification in Pulmonary Sarcomatoid Carcinoma , 2019, Lung Cancer.

[27]  Xiaojing Ma,et al.  Targeting EZH2 Enhances Antigen Presentation, Antitumor Immunity, and Circumvents Anti–PD-1 Resistance in Head and Neck Cancer , 2019, Clinical Cancer Research.

[28]  Yibo Gao,et al.  PD-L1 and CD47 co-expression in pulmonary sarcomatoid carcinoma: a predictor of poor prognosis and potential targets of future combined immunotherapy , 2019, Journal of Cancer Research and Clinical Oncology.

[29]  Jie Yang,et al.  Tepotinib in Non‐Small Cell Lung Cancer with MET Exon 14‐Skipping Mutations or MET Amplification: a Phase 2 Trial in Progress: OA06 , 2018, The New England journal of medicine.

[30]  P. V. Van Schil,et al.  Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. , 2018, Annals of oncology : official journal of the European Society for Medical Oncology.

[31]  D. Jackson,et al.  MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma , 2018, Science Translational Medicine.

[32]  J. Wargo,et al.  The RNA-binding Protein MEX3B Mediates Resistance to Cancer Immunotherapy by Downregulating HLA-A Expression , 2018, Clinical Cancer Research.

[33]  Ping Yang,et al.  Sarcomatoid Carcinoma of the Lung: The Mayo Clinic Experience in 127 Patients , 2017, Clinical lung cancer.

[34]  G. Rossi,et al.  Inter-relationship between PD-L1 expression and clinic-pathological features and driver gene mutations in pulmonary sarcomatoid carcinomas. , 2017, Lung cancer.

[35]  Hongyu Liu,et al.  Clinical Significance and Next-Generation Sequencing of Chinese Pulmonary Sarcomatoid Carcinoma , 2017, Scientific Reports.

[36]  P. Stephens,et al.  Pulmonary Sarcomatoid Carcinomas Commonly Harbor Either Potentially Targetable Genomic Alterations or High Tumor Mutational Burden as Observed by Comprehensive Genomic Profiling , 2017, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[37]  F. Khuri,et al.  Pulmonary Sarcomatoid Carcinoma: An Analysis of the National Cancer Data Base , 2015, Clinical lung cancer.

[38]  J. Mazières,et al.  Characteristics and Clinical Outcomes of Sarcomatoid Carcinoma of the Lung. , 2016, Clinical lung cancer.

[39]  C. Hamard,et al.  Sarcomatoid lung carcinomas show high levels of programmed death ligand-1 (PD-L1) and strong immune-cell infiltration by TCD3 cells and macrophages. , 2016, Lung cancer.

[40]  Jian-Hua Fu,et al.  Characteristics and Prognostic Analysis of 69 Patients With Pulmonary Sarcomatoid Carcinoma , 2016, American journal of clinical oncology.

[41]  J. Jen,et al.  Molecular characterization of pulmonary sarcomatoid carcinoma: analysis of 33 cases , 2016, Modern Pathology.

[42]  M. Shipp,et al.  NLRC5/MHC class I transactivator is a target for immune evasion in cancer , 2016, Proceedings of the National Academy of Sciences.

[43]  A. Borczuk,et al.  Recent advances in the management of pulmonary sarcomatoid carcinoma , 2016, Expert review of respiratory medicine.

[44]  F. Cunningham,et al.  The Ensembl Variant Effect Predictor , 2016, bioRxiv.

[45]  Morten Nielsen,et al.  Gapped sequence alignment using artificial neural networks: application to the MHC class I system , 2016, Bioinform..

[46]  T. Mok,et al.  MET Amplification and Exon 14 Splice Site Mutation Define Unique Molecular Subgroups of Non–Small Cell Lung Carcinoma with Poor Prognosis , 2016, Clinical Cancer Research.

[47]  G. Frampton,et al.  MET 14 Deletion in Sarcomatoid Non-Small-Cell Lung Cancer Detected by Next-Generation Sequencing and Successfully Treated with a MET Inhibitor. , 2015, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[48]  Todd M. Allen,et al.  Distinct Escape Pathway by Hepatitis C Virus Genotype 1a from a Dominant CD8+ T Cell Response by Selection of Altered Epitope Processing , 2015, Journal of Virology.

[49]  Steven J. M. Jones,et al.  Comprehensive molecular profiling of lung adenocarcinoma , 2014, Nature.

[50]  Jerome H. Kim,et al.  Designing the epitope flanking regions for optimal generation of CTL epitopes. , 2014, Vaccine.

[51]  M. Ernstoff,et al.  VISTA is an immune checkpoint molecule for human T cells. , 2014, Cancer research.

[52]  N. Girard,et al.  Efficacy of First-Line Chemotherapy in Patients with Advanced Lung Sarcomatoid Carcinoma , 2013, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[53]  M. Fassan,et al.  Molecular Typing of Lung Adenocarcinoma on Cytological Samples Using a Multigene Next Generation Sequencing Panel , 2013, PloS one.

[54]  Alessandro Sette,et al.  Properties of MHC Class I Presented Peptides That Enhance Immunogenicity , 2013, PLoS Comput. Biol..

[55]  D. Rimm,et al.  Sarcomatoid Lung Carcinomas Show High Levels of Programmed Death Ligand-1 (PD-L1) , 2013, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[56]  Steven J. M. Jones,et al.  Comprehensive genomic characterization of squamous cell lung cancers , 2012, Nature.

[57]  Austin Miller,et al.  Outcomes of sarcomatoid carcinoma of the lung: a Surveillance, Epidemiology, and End Results Database analysis. , 2012, Surgery.

[58]  G. Schackert,et al.  Tumor Evasion from T Cell Surveillance , 2011, Journal of biomedicine & biotechnology.

[59]  R. Tampé,et al.  The TAP translocation machinery in adaptive immunity and viral escape mechanisms. , 2011, Essays in biochemistry.

[60]  B. Seliger,et al.  Identification of E2F1 as an Important Transcription Factor for the Regulation of Tapasin Expression* , 2010, The Journal of Biological Chemistry.

[61]  Clemencia Pinilla,et al.  Derivation of an amino acid similarity matrix for peptide:MHC binding and its application as a Bayesian prior , 2009, BMC Bioinformatics.

[62]  P. Kangueane Bioinformation Discovery: Data to Knowledge in Biology , 2009 .

[63]  H. Min,et al.  Palliative chemotherapy for pulmonary pleomorphic carcinoma. , 2007, Lung cancer.

[64]  F. Garrido,et al.  LOH at 6p21.3 region and HLA class altered phenotypes in bladder carcinomas , 2006, Immunogenetics.

[65]  P. Easterbrook,et al.  CD8+ T Cell Epitope-Flanking Mutations Disrupt Proteasomal Processing of HIV-1 Nef1 , 2005, The Journal of Immunology.

[66]  O. Lund,et al.  The role of the proteasome in generating cytotoxic T-cell epitopes: insights obtained from improved predictions of proteasomal cleavage , 2005, Immunogenetics.

[67]  F. Garrido,et al.  Distribution of HLA class I altered phenotypes in colorectal carcinomas: high frequency of HLA haplotype loss associated with loss of heterozygosity in chromosome region 6p21 , 2004, Immunogenetics.

[68]  P. Kloetzel,et al.  Hepatitis C virus mutation affects proteasomal epitope processing. , 2004, The Journal of clinical investigation.

[69]  Federico Garrido,et al.  MHC class I antigens, immune surveillance, and tumor immune escape , 2003, Journal of cellular physiology.

[70]  O. Lund,et al.  novel sequence representations Reliable prediction of T-cell epitopes using neural networks with , 2003 .

[71]  S. Brunak,et al.  Prediction of proteasome cleavage motifs by neural networks. , 2002, Protein engineering.

[72]  K. Rock,et al.  Sequences That Flank Subdominant and Cryptic Epitopes Influence the Proteolytic Generation of MHC Class I-Presented Peptides1 , 2000, The Journal of Immunology.

[73]  W. Rosenberg Mechanisms of immune escape in viral hepatitis , 1999, Gut.

[74]  Robert Huber,et al.  Contribution of Proteasomal β-Subunits to the Cleavage of Peptide Substrates Analyzed with Yeast Mutants* , 1998, The Journal of Biological Chemistry.

[75]  J. Sidney,et al.  HLA supertypes and supermotifs: a functional perspective on HLA polymorphism. , 1998, Current opinion in immunology.

[76]  D. Wolf,et al.  The Active Sites of the Eukaryotic 20 S Proteasome and Their Involvement in Subunit Precursor Processing* , 1997, The Journal of Biological Chemistry.

[77]  M. Sanda,et al.  Molecular characterization of defective antigen processing in human prostate cancer. , 1995, Journal of the National Cancer Institute.

[78]  W. Bodmer,et al.  Beta 2-microglobulin gene mutations: a study of established colorectal cell lines and fresh tumors. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[79]  J. Yewdell,et al.  Identification of human cancers deficient in antigen processing , 1993, The Journal of experimental medicine.

[80]  J. P. Royston,et al.  Algorithm AS 181: The W Test for Normality , 1982 .

[81]  D. Bauer Constructing Confidence Sets Using Rank Statistics , 1972 .

[82]  Ton N Schumacher,et al.  Cancer Neoantigens. , 2019, Annual review of immunology.

[83]  M. Boudaya,et al.  Pulmonary Sarcomatoid carcinoma: a surgical diagnosis and prognostic factors. , 2019, La Tunisie medicale.