Abstract
Sinonasal intestinal-type adenocarcinoma (ITAC) is a rare malignancy strongly associated with occupational exposure to wood dust that shares morphological and molecular similarities with colorectal adenocarcinoma. Standard treatments offer limited benefit for advanced or recurrent disease. It is therefore necessary to develop other strategies, such as immunotherapies, which require a better understanding of the tumor immune microenvironment, are needed. In this study, we investigated the immune microenvironment of ITACs (n=59), focusing on tumor-infiltrating T lymphocytes (TILs) and macrophages, in situ using immunohistochemistry, ex vivo by multiparametric flow cytometry, as well as by transcriptomic profiling. High CD8⁺ T-cell densities were associated with significantly improved disease-free and overall survival and emerged as an independent prognostic factor. These TILs express immune checkpoints (IC), the most highly expressed being PD1, TIGIT, and TIM-3. Furthermore, TIM-3 was not only expressed by TILs but also by immunoregulatory macrophages, and may represent an important immune escape mechanism in ITACs, since TIM-3 blockade in patient-derived explants led to increased tumor cell apoptosis. Tumor cells strongly expressed CD155 (TIGIT ligand) but not PDL1 (PD1 ligand); however expressed by myeloid cells. Finally, transcriptomic analyses identified one cluster displaying features of "hot tumors" characterized by adaptive immune activation, a better prognosis, and a higher immunotherapy response score, and another cluster with features of "cold tumors". These first exploratory and descriptive findings in ITACs provide a rationale for further investigations using ex vivo and in vivo models to evaluate the therapeutic potential of immunotherapies in these rare cancers.