Page 24 - Helicobacter pylori and Gastric Cancer: From Tumor microenvironment to Immunotherapy

Chapter 1
General introduction
the extensive literature on the action of Sonic Hedgehog proteins and their downstream targets exists, the body of contemporary biomedical literature has not yet been systematically analyzed about the role of the morphogen in gastric pathophysiology. Nevertheless, it is clear that Sonic Hedgehog is highly expressed in gastric cancer cell lines(55). Although increased levels of Sonic Hedgehog have been reported in gastric cancers, its specific role in gastric transformation appears elusive but carries significance because of the availability of Hedgehog antagonists.
In this context is important to note that the phenotype of infiltrating myeloid cells in inflammatory reactions changes over time as to generate MDSCs (myeloid-derived suppressor cells). The latter are a heterogeneous group of immune cells from the myeloid lineage that possesses strong immunosuppressive activities rather than immuno stimulatory properties. Although their mechanisms of action are not clear yet, it is clear that cancer tissues with high infiltration of MDSCs are associated with poor patient prognosis and resistance to therapies. Importantly MDSC generation requires Hedgehog signaling. Expression of GLI1 (a pivotal transcription factor in canonical Hedgehog signaling), is an early indicator that the myeloid cells recruited during chronic inflammation are transforming towards a MDSC phenotype in the stomach(56-59). The ability to track these cell types in the pre-neoplastic state broadens options for the more efficient screening of subjects predisposed to develop gastric cancer eventually as well as to expand opportunities for prophylactic therapy once atrophic gastritis develops, including antagonists of mTOR (mechanistic antagonist of rapamycin)(60-62). Although Hedgehog antagonists been used for other cancer types, their use in clinical trials for gastric cancer is still in its infancy (63). Where initiated, those tests appear to focus on targeting CD44-positive gastric stem cells to treat metastatic disease(64). In this thesis, I shall systematically address the potential promise of such work.
Immune checkpoint blockade and Gastric Cancer
MDSC may well have a negative influence on the course of gastric cancer by impairing immune responses to the oncological process. But also aberrant activation of other immune controlling mechanisms may well have important negative contributions here. Such mechanisms are now often called “checkpoints” which refers to a broad spectrum of either co-receptors or ligands that are widely expressed by immune cells. Importantly, such checkpoints regulate immune cell activation. The “inhibitory checkpoints” represent those molecules that play an important role
22
17