Tumor-immune associations in gastroesophageal cancer: Identifying cancer-intrinsic and immunological determinants of treatment response in gastroesophageal adenocarcinoma

Gastroesophageal adenocarcinoma (GEA) is an aggressive malignancy in which therapeutic progress has been limited. Increasing evidence suggests that the tumor immune microenvironment (TME) plays a central role in prognosis and treatment efficacy. This thesis investigated the interaction between genomic alterations, the TME, and treatment response in gastric and esophageal cancer. Comprehensive immune profiling of The Cancer Genome Atlas–defined molecular subtypes revealed pronounced subtype-specific differences in immune infiltration as well as substantial within-subtype heterogeneity. Tumors with chromosomal instability, the most prevalent subtype, were frequently characterized by an immune-excluded phenotype that was associated with CCNE1 amplification, whereas approximately half of genome-stable tumors contained tumor-associated tertiary lymphoid structures. In relation to response to neoadjuvant chemoradiotherapy in patients with locally advanced esophageal adenocarcinoma, pretreatment biopsies with high intratumoral T-cell infiltration, close spatial proximity of T cells to tumor cells, and a high lymphocyte-to-macrophage ratio were associated with a favorable histopathological response. In addition, several genomic correlates of response were identified; however, these alterations were infrequent and of limited clinical utility. Using an immunocompetent preclinical murine cancer model, VEGFA overexpression was shown to alter the TME and induce primary resistance to PD-1 blockade. Finally, immune profiling in a phase II trial of pembrolizumab in advanced esophageal cancer was limited by a low response rate, although pre-treatment elevated circulating CXCL10 levels did appear to be a robust predictor of improved outcomes. Overall, this work demonstrates that immune contexture, rather than single genomic alterations, is a key determinant of therapeutic response in gastroesophageal cancer, highlighting the need for TME-informed treatment strategies.