Page 174 - Helicobacter pylori and Gastric Cancer: From Tumor microenvironment to Immunotherapy

Chapter 8
Chapter 8
identification of patients that will benefit from such a therapy. In addition, characterization of the tumor microenvironment and T cell cytotoxic functions may prove sensitive prognostic markers. Mono-therapy with Avelumab revealed an acceptable antitumor broad spectrum of activity, safety, and efficacy in gastric cancer patients. In a dose-escalation study involving MEDI4736. It has demonstrated an enhance antitumor activity and safety. Ongoing multicenter trials and development of MEDI4736 as a single therapy is ongoing. MPDL3280A was well accepted with enhanced efficacy, safety, and antitumor activity. No adverse events were recorded in the MPDL3280A trial as the interaction between PD-1 and PD-L2 is not affected in response to MPDL3280A. Now that my analysis revealed a relationship between Hedgehog signaling and immune signal transduction, it may be tempting to combine modulators of Hedgehog signaling with checkpoint-directed therapy.
I propose a sonic hedgehog-initiated novel signaling pathway through Src–Rac cascades, which regulates actin cytoskeletal reorganization and endocytosis. In this framework, Smo coheres to and sequesters Rac in its active form when engaged with for instance the pharmacological compound Purmophamine (B) or Src. Smoothened is released from Patched inhibition in the presence of Sonic Hedgehog which is mediated by Gli-dependent transcriptional activity. Other extracellular signals might regulate secretion of Sonic Hedgehog at particular sites and times. Remarkably, Src and histamine have been shown to trigger Sonic Hedgehog secretion[53], inducing Ca2+ influx in the endothelial cells[54]. Suggesting the Sonic Hedgehog secretion in the fibroblast cells due to the Ca2+ influx. Calcium has repeatedly been reported to induce expression of Hedgehog ligands. It was reported that Ca2+ chelation inhibits Indian Hedgehog gene expression in chick chondrocytes [55]. We describe the impact of subcellular localization of Smoothened on its signaling ability and its chemotactic signaling capacity through a non-canonical pathway, and I feel small mutations in Smoothened may cause its activation in various cancers (but probably not gastric cancer). Importantly, pharmacological activation of Smoothened will activate immune relevant signaling and thus support anti-cancer immunity.
My thesis also contributes to gastric cancer prevention. Gastric atrophy is thought to be a precursor for malignant neoplasm formation. Therefore, enhancements in techniques used for atrophy diagnosis might help identifying individuals at risk for gastric cancer. My findings have thus relevance for recommendations with respect to the examination and grading of atrophy. This will envisage in-depth histologic
168
172