Protein citrullination as a source of cancer neoantigens
Background Citrulline post-translational modification of proteins is mediated by protein arginine deiminase (PADI) family members and has been associated with autoimmune diseases. The role of PADI-citrullinome in immune response in cancer has not been evaluated. We hypothesized that PADI-mediated ci...
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2021
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oai:doaj.org-article:65be92c8f6ac418b8232f5690477e5372021-11-08T05:30:06ZProtein citrullination as a source of cancer neoantigens10.1136/jitc-2021-0025492051-1426https://doaj.org/article/65be92c8f6ac418b8232f5690477e5372021-06-01T00:00:00Zhttps://jitc.bmj.com/content/9/6/e002549.fullhttps://doaj.org/toc/2051-1426Background Citrulline post-translational modification of proteins is mediated by protein arginine deiminase (PADI) family members and has been associated with autoimmune diseases. The role of PADI-citrullinome in immune response in cancer has not been evaluated. We hypothesized that PADI-mediated citrullinome is a source of neoantigens in cancer that induces immune response.Methods Protein expression of PADI family members was evaluated in 196 cancer cell lines by means of indepth proteomic profiling. Gene expression was assessed using messenger RNA data sets from The Cancer Genome Atlas. Immunohistochemical analysis of PADI2 and peptidyl-citrulline was performed using breast cancer tissue sections. Citrullinated 12–34-mer peptides in the putative Major Histocompatibility Complex-II (MHC-II) binding range were profiled in breast cancer cell lines to investigate the relationship between protein citrullination and antigen presentation. We further evaluated immunoglobulin-bound citrullinome by mass spectrometry using 156 patients with breast cancer and 113 cancer-free controls.Results Proteomic and gene expression analyses revealed PADI2 to be highly expressed in several cancer types including breast cancer. Immunohistochemical analysis of 422 breast tumor tissues revealed increased expression of PADI2 in ER− tumors (p<0.0001); PADI2 protein expression was positively correlated (p<0.0001) with peptidyl-citrulline staining. PADI2 expression exhibited strong positive correlations with a B cell immune signature and with MHC-II-bound citrullinated peptides. Increased circulating citrullinated antigen–antibody complexes occurred among newly diagnosed breast cancer cases relative to controls (p=0.0012).Conclusions An immune response associated with citrullinome is a rich source of neoantigens in breast cancer with a potential for diagnostic and therapeutic applications.Makoto KobayashiJody VykoukalHiroyuki KatayamaJames LongJinsong LiuEhsan IrajizadNikul PatelXiangying MaoLeona RuslingYining CaiFuchung HsiaoChuan-Yih YuFranscisco EstevaJohannes FahrmannSam HanashAlejandro M SevillanoBMJ Publishing GrouparticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENJournal for ImmunoTherapy of Cancer, Vol 9, Iss 6 (2021) |
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DOAJ |
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DOAJ |
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EN |
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 |
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Makoto Kobayashi Jody Vykoukal Hiroyuki Katayama James Long Jinsong Liu Ehsan Irajizad Nikul Patel Xiangying Mao Leona Rusling Yining Cai Fuchung Hsiao Chuan-Yih Yu Franscisco Esteva Johannes Fahrmann Sam Hanash Alejandro M Sevillano Protein citrullination as a source of cancer neoantigens |
| description |
Background Citrulline post-translational modification of proteins is mediated by protein arginine deiminase (PADI) family members and has been associated with autoimmune diseases. The role of PADI-citrullinome in immune response in cancer has not been evaluated. We hypothesized that PADI-mediated citrullinome is a source of neoantigens in cancer that induces immune response.Methods Protein expression of PADI family members was evaluated in 196 cancer cell lines by means of indepth proteomic profiling. Gene expression was assessed using messenger RNA data sets from The Cancer Genome Atlas. Immunohistochemical analysis of PADI2 and peptidyl-citrulline was performed using breast cancer tissue sections. Citrullinated 12–34-mer peptides in the putative Major Histocompatibility Complex-II (MHC-II) binding range were profiled in breast cancer cell lines to investigate the relationship between protein citrullination and antigen presentation. We further evaluated immunoglobulin-bound citrullinome by mass spectrometry using 156 patients with breast cancer and 113 cancer-free controls.Results Proteomic and gene expression analyses revealed PADI2 to be highly expressed in several cancer types including breast cancer. Immunohistochemical analysis of 422 breast tumor tissues revealed increased expression of PADI2 in ER− tumors (p<0.0001); PADI2 protein expression was positively correlated (p<0.0001) with peptidyl-citrulline staining. PADI2 expression exhibited strong positive correlations with a B cell immune signature and with MHC-II-bound citrullinated peptides. Increased circulating citrullinated antigen–antibody complexes occurred among newly diagnosed breast cancer cases relative to controls (p=0.0012).Conclusions An immune response associated with citrullinome is a rich source of neoantigens in breast cancer with a potential for diagnostic and therapeutic applications. |
| format |
article |
| author |
Makoto Kobayashi Jody Vykoukal Hiroyuki Katayama James Long Jinsong Liu Ehsan Irajizad Nikul Patel Xiangying Mao Leona Rusling Yining Cai Fuchung Hsiao Chuan-Yih Yu Franscisco Esteva Johannes Fahrmann Sam Hanash Alejandro M Sevillano |
| author_facet |
Makoto Kobayashi Jody Vykoukal Hiroyuki Katayama James Long Jinsong Liu Ehsan Irajizad Nikul Patel Xiangying Mao Leona Rusling Yining Cai Fuchung Hsiao Chuan-Yih Yu Franscisco Esteva Johannes Fahrmann Sam Hanash Alejandro M Sevillano |
| author_sort |
Makoto Kobayashi |
| title |
Protein citrullination as a source of cancer neoantigens |
| title_short |
Protein citrullination as a source of cancer neoantigens |
| title_full |
Protein citrullination as a source of cancer neoantigens |
| title_fullStr |
Protein citrullination as a source of cancer neoantigens |
| title_full_unstemmed |
Protein citrullination as a source of cancer neoantigens |
| title_sort |
protein citrullination as a source of cancer neoantigens |
| publisher |
BMJ Publishing Group |
| publishDate |
2021 |
| url |
https://doaj.org/article/65be92c8f6ac418b8232f5690477e537 |
| work_keys_str_mv |
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