Sushim Mishra

Background: Esophageal squamous cell carcinoma (ESCC) is the sixth-leading cause of cancer-related death worldwide, primarily affecting Eastern Asia and Southern Africa.¹⁰ The 5-year prognosis for ESCC is considerably low at 15 to 25 percent, often because of drug therapy resistance that is correlated with the tumor microenvironment.¹ The tumor microenvironment (TME) consists of cancer cells, surrounding host cells (e.g. fibroblasts and immune cells), and non-cellular components (e.g. cytokines and vesicles), and it influences tumorigenic processes like proliferative signaling and metastasis.⁶   The use of artificial intelligence (AI), RNA sequencing, and Imaging Mass Cytometry (IMC) have identified TME biomarkers directly contributing to treatment resistance, including PD-L1 (programmed death-1 ligand), TAMs (tumor-associated macrophages), and MDSCs (myeloid-derived suppressor cells).⁹ These findings could suggest new therapeutic targets for treating ESCC that limits time spent in surgery, chemotherapy, and radiotherapy.

Objective: In this review, we explore the molecular components of the TME at the single-cell level that greatly affect the prognosis of patients living with ESCC, and how they influence potential treatment of the cancer.

Search Methods: An online search in the PubMed database was conducted from 2017 to 2024 using the following keywords: “tumor microenvironment [Mesh]”, “esophageal squamous cell carcinoma”, “drug therapy resistance”, and “single-cell sequencing”.

Results: In a study utilizing single-cell RNA and T-cell receptor sequencing, ESCC tumors had more epithelial cells and pericytes and less fibroblasts than surrounding normal tissue.² The Mucosal expression program, consisting of germinal center B-cells in tertiary lymphoid structures (TLS) and CXCL17 gene expression, was found to contribute the most to antitumor immunity.² Additionally, platelet-derived growth factor B (PDGF-B) gene expression by endothelial cells stimulated pericyte-myofibroblast transformation, increasing the anti-tumor response.²  More studies looked at the interactions of important tumor biomarkers with ESCC through qRT-PCR and immunohistochemical staining. FOXO1 was paradoxically pro-tumorigenic as it stimulated M0-to-M2 macrophage polarization via CSF-1 and infiltration into tissues via CCL20.³ These macrophages secreted anti-inflammatory cytokines and caused pro-growth metabolism through CCL18, activating the FAK/PI3K/AKT signaling pathway.³ On the other hand, chemoradiotherapy (CRT) significantly increased PD-1 expression of CD4⁺ and CD8⁺ T-cells while stimulating intra-tumoral infiltration, which correlated with favorable survival.⁴ CRT also decreased PD-1 expression of regulatory T-cells and accumulation of TAMs in tissue.⁴  In a study looking at which biomarkers correlated with greater survival rates of ESCC when given neoadjuvant chemo-immunotherapy, ɑSMA⁺ myofibroblasts, CD8⁺ T-cells, and CXCL13⁺ B-cells contributed to a favorable prognosis.¹ A potential treatment (LD-AET) that manipulated the TME was tested in mice with various cancers, and it inhibited the trafficking of MDSCs into tissue, instead stimulating its differentiation into interstitial macrophages that reduced the likelihood of metastasis and reactivation of resected tumor.⁵

Conclusions: The tumor microenvironment (TME) has many localized elements that have antagonizing effects, with some promoting tumor growth (e.g. tumor-associated macrophage (TAM) and myeloid-derived suppressor cell (MSDC) accumulation in tissue) and others being important for tumor suppression (e.g. CD8⁺ T-cells and CXCL13⁺ B-cells). RNA sequencing and imaging mass cytometry have been used to identify other biomarkers that correlate with favorable prognosis, including ɑSMA⁺ myofibroblasts and PDGF-B gene expression. Treatment utilizing the TME is relatively underdeveloped, but there is a lot of potential in therapies targeting biomarkers like MDSCs that can increase rates of progression-free survival.

Works Cited:

1. Wu C, Zhang G, Wang L, et al. Spatial proteomic profiling elucidates immune determinants of neoadjuvant chemo-immunotherapy in esophageal squamous cell carcinoma. Oncogene. 2024;43(37):2751-2767. Published 2024 August 9. doi:10.1038/s41388-024-03123-z
2. Zhang X, Peng L, Luo Y, et al. Dissecting esophageal squamous-cell carcinoma ecosystem by single-cell transcriptomic analysis. Nat Commun. 2021;12(1):5291. Published 2021 Sep 6. doi:10.1038/s41467-021-25539-x
3. Wang Y, Lyu Z, Qin Y, et al. FOXO1 promotes tumor progression by increased M2 macrophage infiltration in esophageal squamous cell carcinoma. Theranostics. 2020;10(25):11535-11548. Published 2020 Sep 16. doi:10.7150/thno.45261
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