title: Serine Proteases Enhance Immunogenic Antigen Presentation on Lung Cancer Cells.
abstract: Immunotherapies targeting immune checkpoints have proven efficacious in reducing the burden of lung cancer in patients; however, the antigenic targets of these reinvigorated T cells remain poorly defined. Lung cancer tumors contain tumor-associated macrophages (TAM) and neutrophils, which release the serine proteases neutrophil elastase (NE) and proteinase 3 (P3) into the tumor microenvironment. NE and P3 shape the antitumor adaptive immune response in breast cancer and melanoma. In this report, we demonstrate that lung cancer cells cross-presented the tumor-associated antigen PR1, derived from NE and P3. Additionally, NE and P3 enhanced the expression of human leukocyte antigen (HLA) class I molecules on lung cancer cells and induced unique, endogenous peptides in the immunopeptidome, as detected with mass spectrometry sequencing. Lung cancer patient tissues with high intratumoral TAMs were enriched for MHC class I genes and T-cell markers, and patients with high TAM and cytotoxic T lymphocyte (CTL) infiltration had improved overall survival. We confirmed the immunogenicity of unique, endogenous peptides with cytotoxicity assays against lung cancer cell lines, using CTLs from healthy donors that had been expanded against select peptides. Finally, CTLs specific for serine proteases-induced endogenous peptides were detected in lung cancer patients using peptide/HLA-A2 tetramers and were elevated in tumor-infiltrating lymphocytes. Thus, serine proteases in the tumor microenvironment of lung cancers promote the presentation of HLA class I immunogenic peptides that are expressed by lung cancer cells, thereby increasing the antigen repertoire that can be targeted in lung cancer.Cancer Immunol Res; 5(4); 319-29. ©2017 AACR.
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Haley L
authors.initials: HL
authors.lastname: Peters
authors.affiliation: Department of Clinical Cancer Prevention-Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Satyendra C
authors.initials: SC
authors.lastname: Tripathi
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Celine
authors.initials: C
authors.lastname: Kerros
authors.affiliation: Department of Clinical Cancer Prevention-Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Katayama
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Haven R
authors.initials: HR
authors.lastname: Garber
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Lisa S
authors.initials: LS
authors.lastname: St John
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Federico
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ismail M
authors.initials: IM
authors.lastname: Meraz
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Roth
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Boris
authors.initials: B
authors.lastname: Sepesi
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Mourad
authors.initials: M
authors.lastname: Majidi
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Ruisaard
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Karen
authors.initials: K
authors.lastname: Clise-Dwyer
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jason
authors.initials: J
authors.lastname: Roszik
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Don L
authors.initials: DL
authors.lastname: Gibbons
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Swisher
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chantale
authors.initials: C
authors.lastname: Bernatchez
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gheath
authors.initials: G
authors.lastname: Alatrash
authors.affiliation: Department of Clinical Cancer Prevention-Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Samir
authors.initials: S
authors.lastname: Hanash
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas. jmolldre@mdanderson.org.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Molldrem
mesh_terms: D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D015415:Biomarkers; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D056747:Immunomodulation; D016130:Immunophenotyping; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008175:Lung Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008213:Lymphocyte Activation; D010455:Peptides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D057057:Serine Proteases / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D015415:Biomarkers; D016207:Cytokines; D015789:HLA-A2 Antigen; D015395:Histocompatibility Antigens Class I; D010455:Peptides; D057057:Serine Proteases