Plasma cells in human pancreatic ductal adenocarcinoma secrete antibodies against self-antigens

Abstract

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.

Sustained innate interferon is an essential inducer of tertiary lymphoid structures

“…The presence of Ova-specific IgG in the serum suggests that the experimentally induced TLS are functional. This is in line with reports that showed that immunoglobulin production by plasma cells can occur in TLS within tumors [86], [87]. Testing the functionality of TLS is generally a challenging task due to the confounding influence of regional lymph nodes: It is currently impossible to unequivocally determine the individual contribution of lymph nodes and TLS to the immune response.…”

Neoadjuvant chemotherapy is associated with suppression of the B cell-centered immune landscape in pancreatic ductal adenocarcinoma

“…Interestingly, previous studies suggested that TLS can foster B cell differentiation into plasma cells ( 49 , 66 ). In PDAC, several studies indicated the presence of plasma cells based on transcriptomic data and also reported a link between a plasma cell signature and improved survival ( 58 , 70 – 72 ). In this study, we first reported the presence of PDAC-infiltrating CD38 + CD138 + plasma cells, which were markedly reduced in neoadjuvant-treated patients and located mainly outside of TLS.…”

Unraveling the complex interplay between anti-tumor immune response and autoimmunity mediated by B cells and autoantibodies in the era of anti-checkpoint monoclonal antibody therapies

“…Since a large proportion of anti-tumor antibodies recognize intracellular self-antigens ( 28 , 29 ), the mechanism by which the intracellular localization of tumor targets enables an efficient anti-tumor activity of such antibodies remains an enigma. The highly inflammatory and fibrotic conditions within the TME may result in the surface-expression of certain intracellular antigens on tumor cells.…”