ETD

• immune system cells subanalysis
• prognostic implications
• sinonasal intestinal-type adenocarcinoma

Background
Sinonasal intestinal-type adenocarcinoma (ITAC) is a rare malignancy closely associated with occupational exposure to wood and leather dust. In recent years, the tumor immune microenvironment (TIME) has emerged as a critical determinant of disease progression and clinical outcomes; however, evidence regarding the role of the immune infiltrate in ITAC remains scarce and fragmented.

Aim of the study
This study aims to provide a comprehensive characterization of the TIME in ITAC by evaluating the density, spatial distribution and prognostic impact of tumor-infiltrating lymphocytes (TILs) and macrophage populations, specifically exploring macrophage polarization and the CD47-SIRP immune evasion axis.

Materials and Methods
A retrospective analysis was conducted on a multicenter cohort of 52 patients diagnosed with ITAC who underwent primary surgical resection. Tissue samples were evaluated using advanced multiplex brightfield immunohistochemistry and multiplex immunofluorescence techniques. These methods enabled the digital quantification and spatial localization (intratumor vs. stromal compartments) of T lymphocytes (CD4+, CD8+, FOXP3+) and tumor-associated macrophages (TAMs: CD163, CD86, CD47).

Results
The analysis demonstrated that ITAC is predominantly characterized by an “immune-excluded” phenotype. A marked and significant stromal sequestration was observed for both effector (CD4+ and CD8+) and regulatory (FOXP3+) T cells, which failed to effectively penetrate the neoplastic epithelial nests. The absolute density of TILs did not serve as an independent predictor of overall survival (OS). Conversely, the epithelial expression of the CD47 receptor (the “do not eat me” signal) was detected in over half of the cases and emerged as a significant negative prognostic factor associated with shorter survival. Furthermore, the presence of a specific CD163+/CD86+ macrophage population (indicative of a pro-tumorigenic M2-like polarization) proved to be a robust independent predictor of poor prognosis. In the multivariate analysis, this immunological parameter (HR = 7.220) outperformed conventional clinical staging (TNM) in predicting the hazard of death.

Conclusions
This study shifts the prognostic paradigm of ITAC from a purely tumor-centric view to a multi-dimensional model that integrates the immune contexture. The identification of epithelial CD47 expression and M2-polarized macrophages as key drivers of poor prognosis provides a strong biological rationale for future targeted therapeutic strategies, such as the use of anti-CD47 monoclonal antibodies, aimed at overcoming the immunosuppressive barrier and restoring antitumor immunity.