Abstract
Gastric cancer (GC) is one of the most important malignancies worldwide because of its high incidence and mortality. The very low survival rates are mainly related to late diagnosis and limited treatment options. GC is the final clinical outcome of a stepwise process that starts with a chronic and sustained inflammatory reaction mounted in response to Helicobacter pylori infection. The bacterium modulates innate and adaptive immunity presumably as part of the strategies to survive, which favors the creation of an immunosuppressive microenvironment that ultimately facilitates GC progression. T-cell exhaustion, which is characterized by elevated expression of immune checkpoint (IC) proteins, is one of the most salient manifestations of immunosuppressive microenvironments. It has been consistently demonstrated that the tumor-immune microenvironment(TIME)‐exhausted phenotype can be reverted by blocking ICs with monoclonal antibodies. Although these therapies are associated with long-lasting response rates, only a subset of patients derive clinical benefit, which varies according to tumor site. The search for biomarkers to predict the response to IC inhibition is a matter of intense investigation as this may contribute to maximize disease control, reduce side effects, and minimize cost. The approval of pembrolizumab for its use in GC has rocketed immuno-oncology research in this cancer type. In this review, we summarize the current knowledge centered around the immune contexture and recent findings in connection with IC inhibition in GC.
Highlights
Inflammation is an intrinsic feature of cancer, influencing many processes that take place during tumor development and progression [1,2,3]
One of the most important features of the T-cell exhaustion phenomenon is the progressive increase in the amount and diversity of inhibitory receptors expressed on T cells, including PD-1, cytotoxic T-lymphocyte antigen-4 (CTLA-4), lymphocyteactivation gene 3 protein (LAG-3), T-cell immunoglobulin domain and mucin domain (TIM-3), 2B4, CD160, V-domain Ig suppressor of T-cell activation (VISTA), and T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) [72,73,74]
T-cell exhaustion, through the expression of different immune checkpoint (IC), is one of the most salient manifestations of the suppressive TIME. e immuneediting process that takes place during Gastric cancer (GC) initiation and progression, from a proinflammatory state induced by H. pylori or Epstein–Barr virus (EBV) infection towards a suppressive microenvironment, includes upregulation in the expression of ICs that prevent T-cell-mediated elimination of tumor cells. e fact that this exhausted state can be reverted with the use of monoclonal antibodies has revolutionized cancer treatment
Summary
Inflammation is an intrinsic feature of cancer, influencing many processes that take place during tumor development and progression [1,2,3]. H. pylori infection, which is linked to GC of intestinal subtype, the most commonly diagnosed worldwide, triggers chronic and persistent inflammation of the gastric mucosa, characterized by intramural infiltration of inflammatory cells and expression of a vast array of inflammatory mediators [12]. Us, the complex interplay of environment, genetics, infection, and inflammation translates into a very heterogeneous disease at the molecular level [14], which has an impact in the clinical management of the GC patients. In addition to PD-L1, several other parameters currently suggested as biomarkers of potential clinical relevance for predicting the response to ICB are being studied in GC. We provide a summary of the current knowledge centered around the immune contexture and the main findings obtained so far in connection to ICB and predictive biomarkers in GC. Studies in population groups with the same ethnic background but dissimilar access to health care, suggest that biological factors could contribute to explain the mortality and survival of GC [37]
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