Heterogeneity and evolution of tumour immune microenvironment in metastatic gastroesophageal adenocarcinoma

Abstract

Background Tumour immune microenvironment heterogeneity is prevalent in numerous cancers and can negatively impact immunotherapy response. Immune heterogeneity and evolution in gastroesophageal adenocarcinoma (GEA) have not been studied in the past. Methods Together with a multi-region sampling of normal, primary and metastatic tissues, we performed whole exome sequencing, TCR sequencing as well as immune cell infiltration estimation through deconvolution of gene expression signals. Results We discovered high TCR repertoire and immune cell infiltration heterogeneity among metastatic sites, while they were homogeneous among primary and normal samples. Metastatic sites shared high levels of abundant TCR clonotypes with blood, indicating immune surveillance via blood. Metastatic sites also had low levels of tumour-eliminating immune cells and were undergoing heavy immunomodulation compared to normal and primary tumour tissues. There was co-evolution of neo-antigen and TCR repertoire, but only in patients with late diverging mutational evolution. Co-evolution of TCR repertoire and immune cell infiltration was seen in all except one patient. Conclusions Our findings revealed immune heterogeneity and co-evolution in GEA, which may inform immunotherapy decision-making.

Significance of dysregulated M2 macrophage and ESR2 in the ovarian metastasis of gastric cancer

“…In GC, a large body of studies have uncovered that various types of infiltrating subsets of immune cells, such as CD4 + regulatory T cell and tumor-associated macrophage (TAM), are shown to promote cancer progression and metastasis, whereas other immune effector cells including CD8 + cytotoxic T cells, natural killer cells and etc. play the opposite role in this process ( 27 , 28 ). Among the dysregulated immune cell subsets, the immunosuppressive and protumoral M2 macrophage is particularly known to actively promote GC metastasis through various mechanisms ( 29 ).…”

Implications of the Organ-Specific Immune Environment for Immune Priming Effect of Radiotherapy in Metastatic Setting

“…[ 61 , 66 , 67 , 68 ]. In many cancers, the TIME in metastases is more immunosuppressive than that of the primary tumours [ 67 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 ].…”