TY - JOUR
T1 - Serine proteases enhance immunogenic antigen presentation on lung cancer cells
AU - Peters, Haley L.
AU - Tripathi, Satyendra C.
AU - Kerros, Celine
AU - Katayama, Hiroyuki
AU - Garber, Haven R.
AU - John, Lisa St S.
AU - Federico, Lorenzo
AU - Meraz, Ismail M.
AU - Roth, Jack A.
AU - Sepesi, Boris
AU - Majidi, Mourad
AU - Ruisaard, Kathryn
AU - Clise-Dwyer, Karen
AU - Roszik, Jason
AU - Gibbons, Don L.
AU - Heymach, John V.
AU - Swisher, Stephen G.
AU - Bernatchez, Chantale
AU - Alatrash, Gheath
AU - Hanash, Samir
AU - Molldrem, Jeffrey J.
N1 - Publisher Copyright:
© 2017 AACR.
PY - 2017/4
Y1 - 2017/4
N2 - 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 tumorassociated 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.
AB - 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 tumorassociated 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.
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U2 - 10.1158/2326-6066.CIR-16-0141
DO - 10.1158/2326-6066.CIR-16-0141
M3 - Article
C2 - 28254787
AN - SCOPUS:85017204750
SN - 2326-6066
VL - 5
SP - 319
EP - 329
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 4
ER -