Natural antibodies identified as potential anti-tumor agents
- Natural antibodies’ potential
Professor of Genomic Pathology at TMDU
Dr. Ishikawa graduated from the Faculty of Medicine at the University of Tokyo in 2000 and received his PhD in Pathology. He performed postdoctoral research in the Genome Science Division of the Research Center for Advanced Science and Technology at
the University of Tokyo. He became Associate Professor in the Department of Pathology there, and joined TMDU as Professor of Genomic Pathology in 2013.
A: I have been working with my TMDU colleagues to clarify the architecture of B-cell immunity in cancers. B cells, together with Tcells, are subsets of lymphocytes within the immune system. There is substantial evidence that these cells play a pivotal role in the immune system’s fight against cancers, although B-cell activity remains relatively elusive compared to the well-studied T-cell system. In our study in Cell Reports, we initially investigated the global landscape of anti-tumor immunity through an “immunogenetics” approach where antigen receptor repertoires of B and T cells were clarified by next-generation sequencing. We found: (1) highly clonal infiltration of B cells in cancer tissues; (2) prominent IgG-type B cells in tumor tissues;and, (3) substantially different profiles of Bcell repertoire between individuals. We then paid closer attention to the dominant B-cell clones in each cancer case, and artifi cially reconstructed the highly clonal immunoglobulins, or antibodies (Abs). By identifying tumorantigens that correspond to those Abs, we found that, although a portion of B-cell immunity is shaped by abundant cellular auto-antigens, a substantial portion of tumor-resident B cells produce functional Abs. In particular, we identified anti-sulfated glycosaminoglycans (sulfated-GAGs) Abs, which showed robust growth-suppression against gastric cancer cells and a wide variety of other human malignancies.
HSGAG (heparan sulfate glycosaminoglycan) is a common type of sulfated GAGs found on cell surface, and its tumor-specific structures and functions are also hypothesized to date.
A: Gastric carcinoma (GC) is one of the most frequent malignancies worldwide. Diff usetype gastric carcinoma (DGC), which accounts for more than 30% of GCs, shows the worst prognosis among gastric tumors. Although we have identified several frequent genetic mutations in DGCs, including RHOA, targeted therapies against such classically non-druggable proteins have not yet been established. Antitumor immunotherapy has gained considerable attention recently and GCs might also be good candidates for it. Through an integrative analysis of The Cancer Genome Atlas (TCGA) database, we found higher B-cell infiltration specifically in DGC cases compared to other types of GCs; thus, we were motivated to study precise B-cell immunity in cancers by focusing on DGCs.
A:At TMDU, there is a strong focus on cancer research and well-established facilities for supporting translational research. One of TMDU’s goals is to expedite the discovery of new diagnostic tools and treatments to contribute to society and humanity.
A: Although the Abs identified in our study exerted growth-suppressive effects against a wide variety of human malignancies in vitro, their molecular functions and behaviors in vivo are still open questions. Identification of more specific structures of the HSGAG antigens is one of the most important aims of future research to clarify the precise function and safety of the Abs we identified. Also, it is important to perform in-depth evaluation of the safety and efficacy of the anti-HSGAG Abs in in vivo models.
A: One of the most important points of our study is that we identified HSGAGs as the major and functional B-cell antigen in cancer environments. Our findings shed light on the immunologic aspects of HSGAGs and might encourage clinical communities to develop HSGAGs such as heparin as a cancer vaccine. From an optimistic point of view, combined therapies with a state-of-the-art anti-PD-1 immune stimulant and patient stratification based on pre-existing anti-HSGAGs immunity would maximize the efficacies and benefi ts of the heparin as a cancer vaccine. Going forward, the adoption of more extensive profiling of tumor-infi ltrating B cells is expected to pave the way toward understanding tumor immunity, and to help discover tumor antigens and natural anti-tumor Abs to fight against refractory cancers.