Tumor immune microenvironment (TIME) in salivary gand cancer (SGC).

What is it about?

This study explored the tumor immune microenvironment (TIME) across major histological subtypes of salivary gland cancer (SGC) to better understand the biological basis of response and resistance to immune checkpoint inhibitors (ICIs). Although ICIs have been tested in clinical trials for SGC, their efficacy has been inconsistent, and the underlying immune context of each subtype has not been fully characterized. Using archival tumor specimens from patients with SGC, we analyzed five representative pathological subtypes: adenoid cystic carcinoma (ACC), adenocarcinoma not otherwise specified (ANOS), salivary duct carcinoma (SDC), and low- and high-grade mucoepidermoid carcinoma (MEClow and MEChigh). The TIME was comprehensively evaluated using multiplex fluorescent immunohistochemistry, allowing simultaneous spatial assessment of immune effector cells, immune suppressor cells, and immune checkpoint molecules in both tumor and stromal compartments. Tumor mutation burden (TMB) was assessed by next-generation sequencing and correlated with immune cell infiltration. Clear differences in TIME were observed among subtypes. ACC showed minimal infiltration of immune effector cells and low PD-L1 expression, consistent with an “immune desert” phenotype. In contrast, MEChigh demonstrated abundant immune cell infiltration and higher PD-L1 expression, representing an “immune-inflamed” phenotype. ANOS, SDC, and MEClow showed intermediate features, characterized by immune cell accumulation mainly in the stroma rather than within tumor nests, suggesting an “immune-excluded” phenotype. Across subtypes, intratumoral CD8+ T-cell density positively correlated with TMB and PD-L1 expression. These findings highlight substantial heterogeneity in the immune landscape of SGC and provide a biological framework for interpreting previous clinical trial results with ICIs.

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Photo by National Institute of Allergy and Infectious Diseases on Unsplash

Photo by National Institute of Allergy and Infectious Diseases on Unsplash

Why is it important?

This study provides one of the most detailed and systematic evaluations of the tumor immune microenvironment in salivary gland cancer. By demonstrating that TIME differs markedly according to histological subtype, it helps explain why immunotherapy has shown limited or inconsistent efficacy in unselected SGC populations. In particular, identifying ACC as an immune-desert tumor offers a clear biological rationale for its poor response to ICIs, while the immune-inflamed profile of MEChigh supports further investigation of immunotherapy in this subtype. The intermediate, immune-excluded profiles seen in ANOS and SDC suggest that combination strategies may be required to overcome immune resistance.

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