Focal adhesion ribonucleoprotein complex proteins are major humoral cancer antigens and targets in autoimmune diseases

Abstract

Despite the accumulating evidences of the significance of humoral cancer immunity, its molecular mechanisms have largely remained elusive. Here we show that B-cell repertoire sequencing of 102 clinical gastric cancers and molecular biological analyses unexpectedly reveal that the major humoral cancer antigens are not case-specific neo-antigens but are rather commonly identified as ribonucleoproteins (RNPs) in the focal adhesion complex. These common antigens are shared as autoantigens with multiple autoimmune diseases, suggesting a direct molecular link between cancer- and auto-immunity on the focal adhesion RNP complex. This complex is partially exposed to the outside of cancer cell surfaces, which directly evokes humoral immunity and enables functional bindings of antibodies to cancer cell surfaces in physiological conditions. These findings shed light on humoral cancer immunity in that it commonly targets cellular components fundamental for cytoskeletal integrity and cell movement, pointing to a novel modality of immunotherapy using humoral immunological reactions to cancers.

Nucleic acid–triggered tumoral immunity propagates pH‐selective therapeutic antibodies through tumor‐driven epitope spreading

“… 17 To determine the precise chemical structures of the sulfated GAG Ags, we used a GAG library covering diverse sulfation patterns (Figure 1A,B ). We performed GAG ELISA using 30 tumor‐infiltrating dominant Ig clones identified from the repertoire sequencing of 102 gastric cancers 16 , 17 and additional 27 pancreatic cancers (Figure 1A ). Five high‐affinity and five low‐affinity anti‐sulfated GAG clones, including those previously reported, 17 were identified (Figure 1C ; Figure S1B,C ).…”

“…We also searched for protein Ags for the 30 dominant Ig clones found in human gastric or pancreatic cancer environments, discovering 10 protein Ags, including those previously reported (Figure 2 ; Figure S1C ). 16 , 17 The remaining 10 clones were still orphan Igs due to possible difficulties in technical conditioning. Therefore, it was surprisingly shown that half (10/20) of the dominant clones with defined Ags, in human tumor environments, commonly recognized dsGAG.…”

“…Repertoire sequencing and the reconstruction of the tumor‐infiltrating dominant clones as human IgG1 were performed as described previously 16 , 17 (see Methods S1 ). The Ig repertoire sequence data of gastric cancers are deposited in JGAS00000000242.…”

“…We previously clarified a global profile of immune receptor repertoires of tumor‐infiltrating lymphocytes in human cancers, discovering a large number of tumor‐specifically dominant B/plasma cell clones. 16 , 17 It was found that multiple of such clones commonly recognized sulfated glycosaminoglycan (GAG) or focal adhesion ribonucleoprotein (RNP) complex proteins. 16 , 17 Thus, a hypothesis has been achieved that anti‐GAG and anti‐RNP constitute a significant portion of humoral tumor immunity.…”

“… 16 , 17 It was found that multiple of such clones commonly recognized sulfated glycosaminoglycan (GAG) or focal adhesion ribonucleoprotein (RNP) complex proteins. 16 , 17 Thus, a hypothesis has been achieved that anti‐GAG and anti‐RNP constitute a significant portion of humoral tumor immunity. It was warranted to investigate the immunological driving forces for the Abs to dominate in tumor environments as well as their therapeutic applicability for human malignancies.…”