The discussions will focus on anti-cancer vaccine and eradication of chronic inflammation, including mRNA-based vaccines and Japanese expertise of tackling H. pylori.
Masanori Hatakeyama, M.D., Ph.D.
Institute of Microbial Chemistry
Induction of BRCAness by the Helicobacter pylori CagA oncoprotein
Chronic infection with Helicobacter pylori cagA-positive strains plays a causative role in more than 80% of gastric cancer, the third-leading cause of cancer-related deaths. The cagA-encoded CagA protein is delivered into the gastric epithelial cells via bacterial type IV secretion. Delivered CagA is tethered to the inner plasma membrane where it acts as a pro-oncogenic protein scaffold by promiscuously interacting with multiple host proteins, most notably oncogenic phosphatase SHP2 and polarity-regulating kinase PAR1b, and thereby perturbing their functions that stimulates gastric carcinogenesis. Furthermore, we recently found that CagA-mediated inhibition of the PAR1b kinase activity subverts nuclear translocalization of the tumor suppressor BRCA1, causing replication fork instability and inactivation of homologous recombination-mediated repair of DNA double strand break (so called "BRCAness"). CagA-mediated BRCAness induces genome instability that greatly increases the chance of introducing driver gene mutations underlying gastric carcinogenesis.
Eric Tartour, M.D., Ph.D.
Université Paris-Cité, Hôpital Européen Georges Pompidou
Targeting resident memory T cells for therapeutic HPV cancer vaccine.
Tissue-resident memory T cells (Trm) represent a new subset of long-lived memory T cells that remain in tissue and do not recirculate. In a preclinical model of head and neck cancer expressing the E6 and E7 proteins from HPV, we show that intranasal vaccination with a mucosal vector, the B subunit of Shiga toxin coupled to the E7 protein from HPV16, induces local Trm and inhibits the growth of tumor. As Trm do not recirculate, we demonstrate their crucial role in the efficacy of cancer vaccine with parabiosis experiments. We have also identified a novel mucosal adjuvant that can be administered nasally to induce local Trm. To better understand why the nasal route is crucial for Trm induction, we showed that this immunization route and not the intramuscular route induced the chemokine CCL16 by ENT and lung epithelial cells that recruited Trm expressing CXCL16. A mucosal vector to deliver HPV16-derived antigens to mucosal dendritic cells combined with mucosal adjuvant represent novel approaches for the development of therapeutic HPV vaccines.