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.
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.
A promotional role for androgen receptor (AR) signaling in hepatocellular carcinogenesis is emerging. In pre-clinical models, including diethylnitrosamine- (DEN-) induced hepatocellular carcinoma (HCC), anti-androgen therapies delay hepatocarcinogenesis. However, pharmacologic anti-androgen therapy in advanced HCC patients fails, suggesting that AR plays a role in HCC onset. This study aims to characterize AR expression and function throughout DEN-induced liver inflammation and carcinogenesis and evaluate the efficacy of prophylactic AR antagonism to prevent hepatocarcinogenesis. We demonstrate that pharmacologic AR antagonism with enzalutamide inhibits hepatocellular carcinogenesis. With enzalutamide treatment, we observe decreased CYP2E1 expression, reducing DEN-induced hepatocyte death and DNA ethyl-adducts. AR protein expression analyses show that DEN causes an initial upregulation of AR in portal fibroblasts and leukocytes, but not hepatocytes, suggesting that hepatocyte-autonomous AR signaling is not essential for DEN-induced carcinogenesis. Ablating androgen signaling by surgical castration reduced pre-carcinogen Kupffer cell populations but did not alter DEN-mediated immune cell recruitment nor AR expression. In this study, we identified that anti-androgen interventions modulate mutagenic DNA adducts, tumour initiation, and immune cell composition. Additionally, we find that AR expression in hepatocytes is not present during nor required for early DEN-mediated carcinogenesis.
Vestibular schwannomas (VS) are benign tumors that lead to significant neurologic and otologic morbidity. How VS heterogeneity and the tumor microenvironment (TME) contribute to the pathogenesis of these tumors remains poorly understood. We performed scRNA-seq on 15 VS samples, with paired scATAC-seq in six samples. We identified diverse Schwann cell (SC), stromal, and immune populations in the VS TME and found that repair-like and MHC-II antigen presenting subtype SCs are associated with increased myeloid cell infiltrate, implicating a nerve injury-like process. Deconvolution analysis of RNA-expression data from 175 tumors revealed Injury-like tumors are associated with larger tumor size, and scATAC-seq identified transcription factors associated with nerve repair among SCs from Injury-like tumors. Ligand-receptor analysis and functional in vitro experiments suggested that SCs recruit monocytes. Our study indicates that Injury-like SCs may cause tumor growth via myeloid cell recruitment and identifies molecular pathways that may be targeted to prevent tumor progression.
TPS6109 Background: Patients with locally advanced HPV+ OPSCC have a favorable prognosis; however, 10-40% will experience disease recurrence after curative-intent therapy (CIT). 80-90% of cases are caused by HPV genotype 16. HPV16 E7 is a promising HPV target as there is little variation among isolates and high epitope affinities for HLA--A*0201 have been identified. HLA--A*0201 is the most common class I allele in the USA, expressed in 40-50% of people of European descent. We aim to lower the recurrence rate in these patients by activating tumor antigen-specific CD8+ T cells. CUE-101 is a novel fusion protein comprised of HLA--A*0201, an HPV16 E7 epitope (aa residues 11-20), a reduced affinity human IL-2 variant, and an effector attenuated human IgG1 Fc domain. In pre-clinical models, CUE--101 demonstrated selective binding, activation, and expansion of HPV16 E711-20-specific CD8+ T cells. In the murine TC-1 tumor model, a murine surrogate of CUE-101 (mCUE--101) increased the frequency of tumor-infiltrating E7-specific CD8+ T cells and improved survival. Animals that remained tumor-free rejected TC-1 tumors upon re-challenge, demonstrating functional immunologic memory. In an ongoing phase 1 trial (NCT03978689) of HLA--A*0201+ patients with recurrent HPV16+ OPSCC, CUE-101 was well tolerated, resulted in expansion of target HPV16 E711-20-specific CD8+ T cells, and showed durable disease control in some patients. In this Phase 2 trial (NCT04852328), CUE-101 will be administered to HLA--A*0201+ patients with HPV16+ OPSCC before CIT. The aims of the trial are to evaluate the safety, tolerability, and pharmacodynamic and immunologic activity of CUE-101 in these patients. Methods: This is a non-randomized Phase 2 trial of three schedules of CUE-101 administered before CIT to HLA--A*0201+ patients with HPV16+ OPSCC. HPV16 status of tumor will be assessed by PCR. Safety assessments will be performed, and blood and tumor samples collected, at baseline and after CUE-101 administration. Following CUE-101, CIT will be administered. Each schedule will enroll 10 patients. CUE-101 (4 mg/kg IV) will be administered 14 days (Schedule A), 14 and 7 days (Schedule B), or 7 days (Schedule C) before day 1 of CIT. If Schedule A is safe and tolerable, Schedule B and then C will commence. A schedule will be deemed safe and tolerable if ≤2 patients experience grade 3-4 TRAEs and/or treatment-related delays of >7 days from the planned date of CIT. Immunologic activity is defined as measurable observation of or increases in HPV16-specific T cells in post-CUE-101 blood and/or tumor samples, relative to baseline, as assessed by either ELISpot or tetramer staining and flow cytometry. Exploratory measures of immune activity will be assessed by single-cell RNAseq and immunofluorescence in tumor samples. A schedule will be considered active if immunologic activity is observed in ≥3 patients. Clinical trial information: NCT04852328 .
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.