High Infiltration of CD68⁺/CD163⁻ Macrophages Is an Adverse Prognostic Factor after Neoadjuvant Chemotherapy in Esophageal and Gastric Adenocarcinoma

Abstract

Tumor-associated macrophages (TAMs) have emerged as key players in tumor immunology but demonstrate a continuum of functional states being either tumor suppressive or promoting. Moreover, chemotherapeutic agents have been shown to alter the tumor microenvironment. Perioperative chemotherapy is a standard treatment option for resectable esophageal and gastric (EG) adenocarcinoma. The aim of this study was to investigate the influence of neoadjuvant chemotherapy (NAC) on TAMs to improve the prognostication and treatment course for these patients. The study cohort comprised 148 patients, all of whom were diagnosed with resectable EG adenocarcinoma and treated with NAC. Immunohistochemistry was applied to assess the total infiltration and infiltration into tumor nests (TN) of CD68⁺/CD163⁻, CD68⁺/CD163⁺, and MARCO⁺ TAMs, on paired biopsies from primary tumors (PT) pre-NAC, and resected PT and lymph node metastases post-NAC. In pre-NAC specimens, high CD68⁺/CD163⁺ infiltration into TN was an unfavorable prognostic factor. No association was found between TAM density in PT pre-NAC and histopathological regression. The density of CD68⁺/CD163⁺ TAMs was increased in PT post-NAC, while the density of MARCO⁺ TAMs was decreased. CD68⁺/CD163⁻ TAM density was not altered. In post-NAC specimens, higher total as well as TN infiltration of CD68⁺/CD163⁻ TAMs were adverse prognostic factors. In conclusion, these results suggest that NAC may alter certain TAM subsets in EG adenocarcinoma, along with their functional properties and thus their prognostic value.