Helicobacter pylori and Gastric Cancer: From Tumor microenvironment to Immunotherapy

Cancer is the generic term used to describe a group of diseases that involve a pathology characterized by abnormal and uncontrolled cell proliferation. Mechanistically, this group of diseases finds its etiology in a disturbance of the cellular signaling pathways that in physiology tightly control tissue compartment size homeostasis but in cancer lose feedback control. The studies presented in this thesis on gastric cancer appear to at least partially support this concept. The survival rate of a gastric cancer patient is dependent on the associated immune parameters within the tumor microenvironment. I feel it constitutes a prognostic marker that can be used to evaluate if an individual is at risk of cancer development, and if the disease has developed can assist in treatment selection. An important goal in this respect that has not yet been satisfactorily reached is to determine a mechanistic signature (expression patterns of immunomodulatory molecules, ratios of immune suppressive cell types over immune effector cell types etcetera) that is associated with either success or failure in immunotherapy. The absence of such a predictive signature now greatly hampers implementation of immune checkpoint therapy in gastric cancer. Hence patients that might benefit from such therapy are being denied access to it whereas patients are not benefiting from immunocheckpoint-directed therapy suffer its side effects. Nevertheless, the emerging capacity to better characterize both cancer cells for neoantigen expression and to precisely phenotype the tumor microenvironment will undoubtedly improve matters in this respect. It is important to stress. However, that final success in the battle against gastric cancer will depend not only on improved therapy in these late phases of the disease. Gastric cancer remains an important contributor to overall mortality and especially cancer-related mortality when viewed globally. To deal with this problem it will be necessary to improve prevention, e.g. by widening opportunities for more active screening of subjects which are predisposed to develop gastric cancer, to improve the efficacy of screening procedures involved and to better understand the gastric cancer process as to open novel avenues for the rational treatment of disease, in particular opportunities for preventive therapy when atrophic gastritis develops should exist. 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 atrophy and should function as a useful assessment tool for evaluation of premetastatic tumor conditions during an endoscopic investigation in routine clinical practice, particularly for patients in developing countries.