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Epithelial-mesenchymal transition (EMT) is a fundamental process that occurs during embryogenesis and tissue repair. However, EMT can be hijacked by malignant cells, where it may promote immune evasion and metastasis. Classically considered a dichotomous transition, EMT in cancer has recently been considered a plastic process whereby malignant cells display and interconvert among hybrid epithelial/mesenchymal (E/M) states. Epithelial-mesenchymal plasticity (EMP) and associated hybrid E/M states are divergent from classical EMT with unique immunomodulatory effects. Here, we review recent insights into the EMP-immune crosstalk, highlighting possible mechanisms of immune evasion conferred by hybrid E/M states and roles of immune cells in EMP.

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Squamous cell carcinoma of the head and neck (HNSCC) affects nearly 500,000 individuals globally each year. With the rise of human papillomavirus (HPV) in the general population, clinicians are seeing a concomitant rise in HPV-related HNSCC. Notably, a hallmark of HPV-related HNSCC is a predilection for unique biological and clinical features, which portend a tendency for hematogenous metastasis to distant locations, such as the brain. Despite the classic belief that HNSCC is restricted to local spread via passive lymphatic drainage, brain metastases (BMs) are a rare complication that occurs in less than 1% of all HNSCC cases. Time between initial diagnosis of HNSCC and BM development can vary considerably. Some patients experience more than a decade of disease-free survival, whereas others present with definitive neurological symptoms that precede primary tumor detection. The authors systematically review the current literature on HNSCC BMs and discuss the current understanding of the effect of HPV status on the risk of developing BMs in the modern genomic era.

Complexities in cell-type composition have rightfully led to skepticism and caution in the interpretation of bulk transcriptomic analyses. Recent studies have shown that deconvolution algorithms can be utilized to computationally estimate cell-type proportions from the gene expression data of bulk blood samples, but their performance when applied to tumor tissues, including those from head and neck, remains poorly characterized. Here, we use single-cell data (~6000 single cells) collected from 21 head and neck squamous cell carcinoma (HNSCC) samples to generate cell-type-specific gene expression signatures. We leverage bulk RNA-seq data from >500 HNSCC samples profiled by The Cancer Genome Atlas (TCGA), and using single-cell data as a reference, apply two newly developed deconvolution algorithms (CIBERSORTx and MuSiC) to the bulk transcriptome data to quantitatively estimate cell-type proportions for each tumor in TCGA. We show that these two algorithms produce similar estimates of constituent/major cell-type proportions and that a high T-cell fraction correlates with improved survival. By further characterizing T-cell subpopulations, we identify that regulatory T-cells (Tregs) were the major contributor to this improved survival. Lastly, we assessed gene expression, specifically in the Treg population, and found that TNFRSF4 (Tumor Necrosis Factor Receptor Superfamily Member 4) was differentially expressed in the core Treg subpopulation. Moreover, higher TNFRSF4 expression was associated with greater survival, suggesting that TNFRSF4 could play a key role in mechanisms underlying the contribution of Treg in HNSCC outcomes.

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