The tumor microenvironment in esophageal cancer and its association with clinical features and neoadjuvant treatment response.

In the era of precision medicine, the tumor microenvironment (TME) of esophageal cancer needs further insight, to identify unfavorable biology leading to poor outcomes. This study analyzed the TME of esophageal cancer in relation to clinicopathologic parameters, and neoadjuvant treatment. A series of patients operated for esophageal cancer with curative intent between 01.2009 and 12.2021 were included. Initial biopsies and surgical specimens of all patients underwent immunohistochemical analysis, to detect the immune infiltrate markers CD3+, CD8, CD163, CD68, PD-L1 and FoxP3+. The CPS score was used for PD-L1 quantification, whereas the Mandard regression grade (TRG) assessed pathologic response to neoadjuvant treatment (NAT). Continuous variables were compared with the Mann-Whitney-U test, and categorical ones with the Chi-2 test; paired-data tests were used when appropriate. Significance threshold was set at p < 0.05. Overall, 68 patients (82.4% males, mean age 62.4±9.4 years, 79.4% adenocarcinoma) were included. TME in smokers had lower M2-like (CD163+, p = 0.010) and total macrophages (CD68+, p = 0.001), but similar CD163/68 ratio and T-cells as non-smokers. Squamous cell cancer compared to adenocarcinoma showed lower M2-like macrophages (p = 0.023) and T-cell infiltration (p = 0.006). NAT increased macrophages in the TME, while depleting Treg/FoxP3 + cells. Poor responders to NAT had similar baseline TME characteristics as complete responders, but they displayed higher total macrophage count (CD68+) after NAT (p = 0.026). In the present series, the TME of active smokers and patients with squamous cell cancer had a significantly reduced M2-like macrophage infiltration. Neoadjuvant treatment recruited macrophages and T-cells in the TME, but interestingly, an increased macrophage count upon final histology was related to poor response to treatment. The present study provides valuable insight to the TME composition of esophageal cancer and its modification after NAT, however, further studies are needed to assess the exact functional role of TME elements, and their impact on clinical outcomes.