Page 25 - Helicobacter pylori and Gastric Cancer: From Tumor microenvironment to Immunotherapy

in preventing over-activation of the immune system and are important to maintaining self-tolerance. In this way, potentially deleterious immune attack by the host immune system can be constrained, but it is clear that at least some cancers pervert this system to escape immunosurveillance. It is well possible that in the context of the gastric cancer cell immune microenvironment, co-inhibitory receptors may pose a threat to the host’s health by preventing an immune response against gastric cancer. Both co-inhibitory receptors and ligands are highly expressed in a large number of malignancies. This high expression allows for successful evasion of antitumor immune responses. One of the most promising tumor immunotherapy strategies is to interrupt these immune “brakes” by blocking antibodies that prevent interactions between receptors and their cognate ligands. As shown by recent clinical trials, targeting either the PD-1/PD-L1 or CTLA-4 pathways have yielded exciting results. However, there remains insufficient study and understanding of specifically gastric cancer in this respect, especially when compared to other malignancies such as melanoma or lung cancer. This consideration has prompted me to explore this aspect of the gastric cancer process as well.
The scope of this thesis
The pivotal role of H. pylori in progression to gastric cancer calls for better understanding of the relation between its genetic make-up and such progression but also a comparison of diagnostic strategies in countries with a relatively high and low incidence of infection with the bacterium. As stated above, the importance of Hedgehog signaling in many forms of cancer and especially in conjunction with its link to gastric cancer developmental processes, has prompted a substantial research effort investigating the potential usefulness of targeting Hedgehog signaling in gastric oncogenesis. As a result, in gastrin-mediated compartment expansion, viral and Helicobacter-dependent gastric carcinogenesis, the role of Hedgehog signaling is now relatively well understood. Furthermore, when the malignant disease is established, the evidence indicates that hedgehog signaling may provoke drug resistance. Now that the hedgehog inhibitor Vismodegib has come available, which has proved useful in other kinds of cancer (especially basal cell carcinoma), it is tempting to propose clinical trials using this compound for patients who have gastric cancer and accordingly various of such studies have now been initiated. As such, this thesis seeks to summarize clinical experiences and outcomes in the ongoing clinical trials of Hedgehog inhibitors, but I also try to obtain insight into the fundamental aspects of signaling by Hedgehog ligands. A similar situation holds
Chapter 1
General introduction
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