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EMT-induced immune evasion: connecting the dots from mechanisms to therapy

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Abstract

Epithelial–mesenchymal transition (EMT) is a dynamic program crucial for organismal development and tissue regeneration. Unfortunately, this program is often hijacked by epithelial tumors to facilitate metastasis. Beyond its role in cancer spread, EMT increases cancer cell survival by activating stem cell programs and bypassing apoptotic programs. Importantly, the capacity of EMT to enforce tumor progression by altering the tumor cell phenotype without triggering immune responses opens the intriguing possibility of a mechanistic link between EMT-driven cancers and immune evasion. Indeed, EMT has been acknowledged as a of driver immune evasion, but the mechanisms are still evolving. Here, we review recent insights into the influence of EMT on tumor immune evasion. Specifically, we focus on the mechanistic roles of EMT in immune escape as the basis that may provide a platform for innovative therapeutic approaches in advanced tumors. We summarize promising therapeutic approaches currently in clinical trials and trending preclinical studies aimed at reinvigorating the tumor microenvironment to create immune-permissive conditions that facilitates immune-mediated tumor clearance. We anticipate that this will assist researchers and pharmaceutical companies in understanding how EMT compromises the immune response, potentially paving the way for effective cancer therapies.

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Abbreviations

EMT:

Epithelial–mesenchymal transition

MET:

Mesenchymal–epithelial transition

TME:

Tumor microenvironment

HLA:

Human leukocyte antigen

CSCs:

Cancer stem cells

EMP:

Epithelial–mesenchymal plasticity

ECM:

Extracellular matrix

EMT-TF:

Epithelial–mesenchymal transition transcription factors

MHC:

Major histocompatibility class

β2M:

β2-microglobulin

CTLS:

Cytotoxic T lymphocytes

TGF-β:

Transforming growth factor beta

TAP:

Transporters associated with antigen processing

IS:

Immunoproteasome

PSMB :

Proteasome subunit beta type

NSCLC:

Nonsmall cell lung cancer

KLRG1:

Killer lectin-like receptor G1

E-cadherin:

Epithelial cadherin

KIRs:

Killer immunoglobin-like receptors

IFN-γ:

Interferon gamma

TCR:

T-cell receptor

LC3:

Light chain 3

ATG:

Autophagy-related

ULK:

Unc-51-like autophagy-activating kinase

CTLA-4:

Cytotoxic T-lymphocyte-associated protein 4

PD-1:

Programmed cell death protein 1

TIM-3:

T-cell immunoglobulin domain and mucin domain-3

LAG-3:

Lymphocyte activation gene 3

TIGIT:

T-cell immunoreceptor with Ig and ITIM domains

APCs:

Antigen presenting cells

PD-L1:

Programmed death ligand

MDSCs:

Myeloid-derived suppressor cells

TRegs:

Regulatory T cells

TAMs:

Tumor-associated macrophages

DCreg:

Regulatory dendritic cells

IDO:

Indoleamine 2,3-dioxygenase

CCL:

Chemokine (CC motif) ligand

CXCL:

Chemokine (CXC motif) ligand

NF-κβ:

Nuclear factor kappa B

CXCR:

CXC chemokine receptor

HDACs:

Histone deacetylases

LSD:

Lysine-specific histone demethylase

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  1. Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, USA

    Sikiru O. Imodoye

  2. Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA

    Kamoru A. Adedokun

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Imodoye, S.O., Adedokun, K.A. EMT-induced immune evasion: connecting the dots from mechanisms to therapy. Clin Exp Med 23, 4265–4287 (2023). https://doi.org/10.1007/s10238-023-01229-4

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