Targeted Therapies in Gastric Cancer: Molecular Signatures and Immune Microenvironment Insights

Despite the constant decline in incidence, gastric cancer (GC) accounts for 4% of all neoplasms in Europe, being the sixth-ranked cancer for incidence (13.7 cases/100,000 individuals) and the fourth for mortality (10.3 deaths/100,000 individuals). GC is widely represented in both sexes as the fifth incident neoplasm among men (19.5 cases/100,000) and the seventh among women (9.3 cases/100,000). Occurrence is characterized by considerable geographical variation, which allows us to distinguish countries with high, intermediate, and low incidence. The incidence also varies with age and peaks in the seventh decade. Beside the overall reduction in incidence, a relative increase in primitive forms with a proximal location is observed, particularly for those arising from the gastroesophageal junction. In Europe, the 5-year survival rate for patients diagnosed with GC is around 25%.

GC is a histologically, molecularly, and immunologically heterogeneous disease. Several targeted therapeutics have been developed for the treatment of unresectable or metastatic GC. Comprehensive characterization of the molecular profile and the tumor immune microenvironment of GC has allowed researchers to explore promising biomarkers for GC treatment. Recently, molecular characterization via “The Cancer Genome Atlas” project has identified 4 subtypes of gastric adenocarcinoma: Epstein-Barr virus (EBV)-positive subtype, microsatellite instability subtype, genomically stable subtype, and chromosomal instability subtype. The subgroup of EBV-positive tumors presents amplification of JAK2, CD274, and PDCD1LG2 genes. CD274 and PDCD1LG2 encode PD-L1 (programmed death-ligand 1) and PD-L2 (programmed death-ligand 2), suggesting a role for PD-1/PD-L1 inhibitors. This has enabled a new paradigm in precision-targeted immunotherapy.

As a biomarker, PD-L1 displays some limitations which may affect its usefulness as a predictor of response to immunotherapy. One of these limitations is the intratumoral heterogeneity of PD-L1 expression. Indeed, PD-L1 expression shows a high rate of discordance between biopsy and surgically resected tissue, and between primary and metastatic tumors. Temporal heterogeneity of PD-L1 expression between tumors before and after chemotherapy has also been reported. Another major limitation is interobserver variation in the assessment of PD-L1 expression. These discrepancies occur even among experienced pathologists. Therefore, standardized and objective methods for assessing PD-L1, such as using artificial intelligence in image analysis, are urgently needed. At the same time, the presence and distribution of tumour-infiltrating lymphocytes (TILs) is a critical biomarker that can be assessed in concert with PD-L1. A high density of TILs and increased CD3+ or CD8+ T cells are associated with a favorable prognosis in patients with GC. Also, the distribution pattern of TILs is crucial for predicting PD-L1 immunotherapy response in various tumors. The concept of three immune phenotypes has been suggested based on the state of TIL distribution in tumors or in the peritumoral stroma: inflamed (TILs localized intratumorally), excluded (TILs retained in the peritumoral stroma), and desert (TILs scattered in both tumor nests and in the stroma). Tumors with an inflamed phenotype showed increased expression of PD-L1 by tumor and immune cells and a better response to ICI treatment compared to other phenotypes. The number of TILs, immune cell subtypes, and their distribution are important factors associated with prognostic significance and may be predictive markers of immunotherapy response.

Understanding the mechanisms of biomarkers, the current diagnostic methods and their limitations, and the implications for targeted therapy response are crucial aspects in precision medicine. A comprehensive examination of these biomarkers in GC can provide better patient stratification and selection, allowing them to benefit from specific targeted therapies, including immunotherapy.

We invite the submission of research articles that may help clarify the mechanisms underlying tumor heterogeneity/microenvironment, the diverse molecular signatures of GC, and the relative contribution of immune system cells. Studies conducted to unveil the molecular alterations exhibited by tumor cells, the proposal of novel targets for cancer therapy, and the mechanisms of action of drugs and drug candidates (including off-target effects and drug repurposing) are also welcome. In addition, we aim to promote the diffusion of review articles highlighting new findings in the above areas and underlining the similarities or cross-comparisons between GC and other human malignancies.



Manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by robust and relevant validation (clinical cohort or biological validation in vitro or in vivo) are out of scope for this topic.