Comprehensive evaluation of the tumor immune microenvironment and its dynamic changes in patients with locally advanced rectal cancer treated with preoperative chemoradiotherapy: From the phase II ADORE study

A better understanding of the effects of preoperative chemoradiotherapy (CRT) on tumor immune microenvironment (TIME) is essential to improve the treatment outcomes of patients with locally advanced rectal cancer (LARC). In this context, we performed a multiplex immunofluorescence staining to evaluate the TIME in 158 patients with LARC who underwent preoperative CRT followed by surgery and adjuvant chemotherapy in the ADORE trial. We found that higher levels of T-cell subsets (CD3⁺, CD4⁺, and CD8⁺) and dendritic cells in the tumor compartment of pretreatment biopsy samples were associated with good response to preoperative CRT. After CRT, there was a significant increase in the densities of CD3⁺ T cells, CD8⁺ T cells, and dendritic cells, while that of CD4⁺FoxP3⁺ regulatory T cells decreased, indicating that CRT changed the TIME into a more immune-active status. However, CRT also conferred an immunosuppressive effect by polarizing the tumor-associated macrophages from pro-inflammatory M1 macrophage to immune-suppressive M2 macrophages and decreasing the density of B cells. High delta values of CD3⁺ T cells and PD-L1⁺ lymphocytes after CRT were associated with good disease-free survival (DFS), while that of CD4⁺FoxP3⁺ regulatory T cells was associated with poor DFS. These findings provide a framework for future studies incorporating strategies to modulate the TIME in patients with LARC.