Plasma cells in human pancreatic ductal adenocarcinoma secrete antibodies to widely expressed self-antigens

Intratumoral B cell responses are associated with more favorable clinical outcomes in human pancreatic ductal adenocarcinoma cancer (PDAC). However, the antigens driving these B cell responses are largely unknown. We sought to discover these antigens by using single-cell RNA (sc-RNASeq) and immunoglobulin (Ig) sequencing of tumor-infiltrating immune cells from seven 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 hyper-mutated 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 tissue, and identified frequent staining of intracellular self-antigens. Three of these antigens were identified: the filamentous actin (F-actin), the nucleic protein, RUVBL2, and the mitochondrial protein, HSPD1. Antibody titers to F-actin and HSPD1 were frequently elevated in the plasma of PDAC patients, and also detectable in healthy donors. Thus, PCs in PDAC frequently produce auto-antibodies reacting with intracellular self-antigens, which may result from promotion of pre-existing autoreactive B cell responses. These observations indicate that the chronic inflammatory microenvironment of PDAC can support the adaptive immune responses. Overall design: single-cell RNA-seq and BCR-seq