Abstract
Survival is difficult to predict in patients with resected stage I lung adenocarcinoma (LUAD), but tumor microenvironment (TME) factors appear useful in predicting survival in advanced non-small cell lung cancer. We aimed to identify the TME factors linked to recurrence/metastasis and survival in stage I LUAD patients. We evaluated TME factors in stage I LUAD patients in The Cancer Genome Atlas (TCGA) using the "ESTIMATE" and "MCP-counter" R packages. We characterized infiltrating immune cells in the tumor and stromal regions in 44 stage I LUAD patients at our hospital using immunohistochemical methods combined with the HALO® Image Analysis Platform. In TCGA LUAD patients, the number of neutrophils was higher in patients without recurrence/metastasis than in patients with recurrence/metastasis. For patients with recurrence/metastasis, higher CD8+ T lymphocyte and B lymphocyte infiltration levels were associated with better overall survival (OS), and myeloid dendritic cell (DC) infiltration was associated with better disease-free survival (DFS). In stage I LUAD patients at our hospital, CD4+ T cells, CD8+ T cells, CD14+ monocytic lineage cells, CD16+ NK cells, and CD19+ B lymphocytes were more highly expressed in stromal regions than in tumor regions. Moreover, high intratumoral CD11c+ myeloid DC and CD68+ macrophage levels were associated with recurrence/metastasis. Within tumor regions, higher CD11c+ myeloid DC and CD68+ macrophage levels were associated with shorter DFS; within stromal regions, higher CD68+ macrophage levels were associated with shorter DFS. Multivariate analysis revealed that the presence of intravascular carcinoma embolus, higher intratumoral CD11c+ myeloid DC levels, and high stromal CD68+ macrophage and CD4+ T-cell levels were independently linked to recurrence/metastasis in stage I LUAD patients. This study using 2 datasets shows that key players in the TME are associated with recurrence/metastasis in stage I LUAD patients. Higher intratumoral CD11c+ myeloid DC, stromal CD68+ macrophage and stromal CD4+ T-cell levels are independent prognostic factors for DFS in these patients.