Plasma cells in human pancreatic ductal adenocarcinoma secrete antibodies against self-antigens
Intratumoral B cell responses are associated with more favorable clinical outcomes in human pancreatic ductal adenocarcinoma (PDAC). However, the antigens driving these B cell responses are largely unknown. We sought to discover these antigens by using single-cell RNA sequencing (scRNA-Seq) and immu...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2023-11-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.172449 |
| _version_ | 1797634259112951808 |
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| author | Min Yao Jonathan Preall Johannes T.-H. Yeh Darryl Pappin Paolo Cifani Yixin Zhao Sophia Shen Philip Moresco Brian He Hardik Patel Amber N. Habowski Daniel A. King Kara Raphael Arvind Rishi Divyesh Sejpal Matthew J. Weiss David Tuveson Douglas T. Fearon |
| author_facet | Min Yao Jonathan Preall Johannes T.-H. Yeh Darryl Pappin Paolo Cifani Yixin Zhao Sophia Shen Philip Moresco Brian He Hardik Patel Amber N. Habowski Daniel A. King Kara Raphael Arvind Rishi Divyesh Sejpal Matthew J. Weiss David Tuveson Douglas T. Fearon |
| author_sort | Min Yao |
| collection | DOAJ |
| description | Intratumoral B cell responses are associated with more favorable clinical outcomes in human pancreatic ductal adenocarcinoma (PDAC). However, the antigens driving these B cell responses are largely unknown. We sought to discover these antigens by using single-cell RNA sequencing (scRNA-Seq) and immunoglobulin (Ig) sequencing of tumor-infiltrating immune cells from 7 primary PDAC samples. We identified activated T and B cell responses and evidence of germinal center reactions. Ig sequencing identified plasma cell (PC) clones expressing isotype-switched and hypermutated Igs, suggesting the occurrence of T cell–dependent B cell responses. We assessed the reactivity of 41 recombinant antibodies that represented the products of 235 PCs and 12 B cells toward multiple cell lines and PDAC tissues and observed frequent staining of intracellular self-antigens. Three of these antigens were identified: the filamentous actin (F-actin), the nucleic protein RuvB like AAA ATPase 2 (RUVBL2), and the mitochondrial protein heat shock protein family D (Hsp60) member 1 (HSPD1). Antibody titers against F-actin and HSPD1 were substantially elevated in the plasma of patients with PDAC compared with healthy donors. Thus, PCs in PDAC produce autoantibodies reacting with intracellular self-antigens, which may result from promotion of preexisting, autoreactive B cell responses. These observations indicate the chronic inflammatory microenvironment of PDAC can support the adaptive immune response. |
| first_indexed | 2024-03-11T12:06:11Z |
| format | Article |
| id | doaj.art-ecd02e7631a843fcb9f7b9f96b213e9d |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:06:11Z |
| publishDate | 2023-11-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-ecd02e7631a843fcb9f7b9f96b213e9d2023-11-07T16:26:23ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-11-01821Plasma cells in human pancreatic ductal adenocarcinoma secrete antibodies against self-antigensMin YaoJonathan PreallJohannes T.-H. YehDarryl PappinPaolo CifaniYixin ZhaoSophia ShenPhilip MorescoBrian HeHardik PatelAmber N. HabowskiDaniel A. KingKara RaphaelArvind RishiDivyesh SejpalMatthew J. WeissDavid TuvesonDouglas T. FearonIntratumoral B cell responses are associated with more favorable clinical outcomes in human pancreatic ductal adenocarcinoma (PDAC). However, the antigens driving these B cell responses are largely unknown. We sought to discover these antigens by using single-cell RNA sequencing (scRNA-Seq) and immunoglobulin (Ig) sequencing of tumor-infiltrating immune cells from 7 primary PDAC samples. We identified activated T and B cell responses and evidence of germinal center reactions. Ig sequencing identified plasma cell (PC) clones expressing isotype-switched and hypermutated Igs, suggesting the occurrence of T cell–dependent B cell responses. We assessed the reactivity of 41 recombinant antibodies that represented the products of 235 PCs and 12 B cells toward multiple cell lines and PDAC tissues and observed frequent staining of intracellular self-antigens. Three of these antigens were identified: the filamentous actin (F-actin), the nucleic protein RuvB like AAA ATPase 2 (RUVBL2), and the mitochondrial protein heat shock protein family D (Hsp60) member 1 (HSPD1). Antibody titers against F-actin and HSPD1 were substantially elevated in the plasma of patients with PDAC compared with healthy donors. Thus, PCs in PDAC produce autoantibodies reacting with intracellular self-antigens, which may result from promotion of preexisting, autoreactive B cell responses. These observations indicate the chronic inflammatory microenvironment of PDAC can support the adaptive immune response.https://doi.org/10.1172/jci.insight.172449ImmunologyOncology |
| spellingShingle | Min Yao Jonathan Preall Johannes T.-H. Yeh Darryl Pappin Paolo Cifani Yixin Zhao Sophia Shen Philip Moresco Brian He Hardik Patel Amber N. Habowski Daniel A. King Kara Raphael Arvind Rishi Divyesh Sejpal Matthew J. Weiss David Tuveson Douglas T. Fearon Plasma cells in human pancreatic ductal adenocarcinoma secrete antibodies against self-antigens JCI Insight Immunology Oncology |
| title | Plasma cells in human pancreatic ductal adenocarcinoma secrete antibodies against self-antigens |
| title_full | Plasma cells in human pancreatic ductal adenocarcinoma secrete antibodies against self-antigens |
| title_fullStr | Plasma cells in human pancreatic ductal adenocarcinoma secrete antibodies against self-antigens |
| title_full_unstemmed | Plasma cells in human pancreatic ductal adenocarcinoma secrete antibodies against self-antigens |
| title_short | Plasma cells in human pancreatic ductal adenocarcinoma secrete antibodies against self-antigens |
| title_sort | plasma cells in human pancreatic ductal adenocarcinoma secrete antibodies against self antigens |
| topic | Immunology Oncology |
| url | https://doi.org/10.1172/jci.insight.172449 |
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