Page 169 - Helicobacter pylori and Gastric Cancer: From Tumor microenvironment to Immunotherapy

Summary
Cancer is the generic term used to describe a group of diseases that involves a pathology characterized by abnormal and uncontrolled cell proliferation. Mechanistically, this group of diseases find 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 resulting growth physically impairs body function and can provoke substantial pain and suffering. To cure disease or at least improve quality of life, it is important to know how cancer patients respond to different treatment options and to develop new treatment modalities as current ones are often still largely inadequate.
Theoretically, one might assume that the changes in genetic make-up that are associated with the cancerous process would create neoantigens and thus tumor cells should be subject to attack by the body’s immune system. Although, there is evidence that many tumors are to a certain extent constrained in their growth by immunity, evidently this control fails in many patients. In this context it is of substantial significance to study the tumor microenvironment as a whole, because it has valuable prognostic potential with respect as to how the disease course will react to the immunogenic mutation load.
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 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 immunocheckpoint therapy in gastric cancer, hence patients that might benefit from such therapy are being denied access to it whereas patients 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 micro-environment will certainly improve matters in this respect. It is important to stress, however, that final
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