Page 171 - Helicobacter pylori and Gastric Cancer: From Tumor microenvironment to Immunotherapy

tumors that can potentially be targeted by stimulation of immune monitoring. This will require full supplementation of information which is still lacking with respect to the multifaceted association between cancer, the tumor surroundings, and the immune system.
Anti-PD-1, Anti-PD-L1 and Anti-CTLA-4-therapy targeting immune checkpoints have delivered hopeful outcomes in some preliminary clinical trials. However, we need to await the results from various ongoing and future clinical trials to properly address its full potential in gastric cancer. Also the possibilities of several synergistic methodologies that may have a beneficial effect (vaccination, cytokine infusions etcetera), either with immunotherapy alone or in further combination with chemotherapy need to be addressed and indeed it appears that such investigations are now starting. Furthermore, plans to ascertain the possibilities offered by potential prognostic biomarkers with respect to the outcome of immunocheckpoint therapy in gastric cancer have already been launched, and I eagerly await the future results of such efforts. In this respect my conclusion is that understanding immune response patterns and better control of immune-therapy-associated side effects will prove vital for widespread adoption in clinical practice for the drugs whose use is now mostly restricted to clinical trials. From the currently available data and its evolving momentum a promising efficacy of immunotherapy agents is revealed but I hope that ongoing clinical trials and preclinical efforts will address the unanswered question I listed above.
In chapter 4 I further explore the mechanistic details that drive Hedgehog signaling, which is an essential morphogen in explaining both physiology and pathology in the gastrointestinal tract. An aspect that has received relatively little attention in the main text of this chapter is that my findings describe a novel signaling cascade functioning through the SRC Homology 3 Domain-containing proteins which, I feel, may be activated directly by Hedgehog ligands but further investigation is necessary to substantiate this notion (e.g. through better analysis of the effects of Hedgehog on the kinome of Patched-deficient fibroblasts, which was not rigoursly done in this thesis). Together, I suggest that Sonic Hedgehog can stimulate Src activity via types I and type II noncanonical signaling pathways and that the latter may resemble ther effects of Hedgehog in axonal guidance in development. Thus I propose a model on the role of Smo interaction with Rho signaling that not only has relevance for the model systems described in this chapter but may also be relevant for formation and regulation of dendritic projections in the neural system (or, who knows, even in
Summary
Summary
165
169
8