Implications of NOVA1 suppression within the microenvironment of gastric cancer: association with immune cell dysregulation

Background: The neuronal splicing factor neuro-oncological ventral antigen 1 (NOVA1) is enriched in normal fibroblasts. Stromal spindle cells such as fibroblasts are major components of tissue inflammation and tertiary lymphoid structures within the microenvironment that contribute to the survival and growth of cancer cells. In the present study, we investigated changes of NOVA1 expression in tertiary lymphoid structures in early and advanced gastric cancer microenvironments in terms of tumor progression and immune regulation. Methods: Using immunohistochemistry, we analyzed NOVA1 expression in tumor cells, T cells, and stromal spindle cells as well as infiltrating densities of CD3⁺ T cells, forkhead box P3 positive (FOXP3⁺) regulatory T cells, CD68⁺ macrophages, CD163⁺ M2 macrophages, and myeloperoxidase-positive neutrophils in 396 surgically resected gastric cancer tissues. Results: Suppressed NOVA1 expression in tumor cells, T cells, and stromal spindle cells was closely related to decreased infiltration of FOXP3⁺ regulatory T cells, increased infiltration of CD68⁺ macrophages and CD163⁺ M2 macrophages, more advanced tumor stage, and inferior overall survival rate. In addition, low infiltration of CD3⁺ T cells and FOXP3⁺ regulatory T cells and high infiltration of CD68⁺ macrophages were associated with inferior overall survival. Specifically, weak NOVA1 expression in tumor cells was independently related to more advanced tumor stage and inferior overall survival. Conclusions: NOVA1 suppression was frequently noted in the gastric cancer microenvironment, and attenuated NOVA1 expression in tumor cells was associated with tumor progression and poor prognosis. This finding seems to be related to immune dysfunction through changes in the immune cell composition of T cells and macrophages.