Tumor microenvironment signaling and therapeutics in cancer progression

Abstract

Tumor development and metastasis are facilitated by the complex interactions between cancer cells and their microenvironment, which comprises stromal cells and extracellular matrix (ECM) components, among other factors. Stromal cells can adopt new phenotypes to promote tumor cell invasion. A deep understanding of the signaling pathways involved in cell-to-cell and cell-to-ECM interactions is needed to design effective intervention strategies that might interrupt these interactions. In this review, we describe the tumor microenvironment (TME) components and associated therapeutics. We discuss the clinical advances in the prevalent and newly discovered signaling pathways in the TME, the immune checkpoints and immunosuppressive chemokines, and currently used inhibitors targeting these pathways. These include both intrinsic and non-autonomous tumor cell signaling pathways in the TME: protein kinase C (PKC) signaling, Notch, and transforming growth factor (TGF-β) signaling, Endoplasmic Reticulum (ER) stress response, lactate signaling, Metabolic reprogramming, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and Siglec signaling pathways. We also discuss the recent advances in Programmed Cell Death Protein 1 (PD-1), Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA4), T-cell immunoglobulin mucin-3 (TIM-3) and Lymphocyte Activating Gene 3 (LAG3) immune checkpoint inhibitors along with the C-C chemokine receptor 4 (CCR4)- C-C class chemokines 22 (CCL22)/ and 17 (CCL17), C-C chemokine receptor type 2 (CCR2)- chemokine (C-C motif) ligand 2 (CCL2), C-C chemokine receptor type 5 (CCR5)- chemokine (C-C motif) ligand 3 (CCL3) chemokine signaling axis in the TME. In addition, this review provides a holistic understanding of the TME as we discuss the three-dimensional and microfluidic models of the TME, which are believed to recapitulate the original characteristics of the patient tumor and hence may be used as a platform to study new mechanisms and screen for various anti-cancer therapies. We further discuss the systemic influences of gut microbiota in TME reprogramming and treatment response. Overall, this review provides a comprehensive analysis of the diverse and most critical signaling pathways in the TME, highlighting the associated newest and critical preclinical and clinical studies along with their underlying biology. We highlight the importance of the most recent technologies of microfluidics and lab-on-chip models for TME research and also present an overview of extrinsic factors, such as the inhabitant human microbiome, which have the potential to modulate TME biology and drug responses.

Keywords: 3D-model; cancer therapy; gut microbiota; immune signaling; metabolism; signaling; tumor microenvironment.

FIGURE 1

Hormones, metabolites and cytokines released by the microenvironment regulate gene expression to increase glucose uptake and glycolysis in the tumor cell. cGAS‐STING cellular signaling pathway is activated upon recognition of double‐stranded DNA in the cytosol. cGAS in turn activates the STING protein on the ER to initiate downstream signaling, primarily through TBK‐1 and IKK. STING activation typically leads to the activation of transcription factors, IRF3 and NF‐κB1, which is known to partially inhibit the activity of NF‐κB1. STING signaling results in the production of IFN‐I and TNF‐α proinflammatory cytokines. Siglec‐sialic (sialidase) axes signaling to represent siglecs on the surface of immune cells and binding with sialic on tumor cell leads to the deactivation of immune response by all the immune cell population as siglec express on most of the immune cell (e.g., T‐cell, TAM, MDSC, NK and neutrophils). Created with BioRender.com Abbreviations: cGAS: cyclic GMP–AMP synthase; STING: stimulator of interferon genes; ER: Endoplasmic Reticulum; TBK‐1: TANK‐binding kinase 1; IKK: nuclear factor‐κB (IκB) kinase; IRF3: Interferon regulatory factor 3; NF‐κB1: nuclear factor κB1; IFN‐I: Type I interferons; TNF‐α: Tumour necrosis factor α; TAM: Tumor‐Associated Macrophage; MDSC: Myeloid‐derived suppressor cell; NK: Natural Killer, TRAF: Tumor‐necrosis factor Receptor‐Associated Factor, TAK: TGF‐β‐activated kinase.

FIGURE 2

Blockade of ICI restores T cell function. Inhibition of PD‐1, CTLA4, TIM‐3, and LAG3 with interaction by antibodies, drugs, and peptides. The cytotoxic signal is released when the TCR recognizes an antigen on the membrane of tumor cells or (APCs). However, PD‐L1/2, B7‐1/2, Gal‐9/BAT‐3 and Gal‐3/α‐syn/L‐selectin/FGL‐1 are up‐regulated in tumor cells (APCs) when T cells are activated, resulting in inhibitory signals and dampening T cell activation by stimulatory signals. Clinical trials of blocking or inhibiting these interactions using antibodies or a newly designed combination, which restores T cell function and anti‐tumor immunity, are ongoing. Created with BioRender.com.Abbreviations: ICI: Immune checkpoint inhibitor; PD‐1: Programmed cell death protein 1; CTLA4: Cytotoxic T‐lymphocyte associated protein 4; TIM‐3: T‐cell immunoglobulin and mucin domain 3; LAG3: Lymphocyte Activating 3; TCR: T cell receptor; APC: Antigen‐presenting cells; PD‐L1/2: ligands of PD‐1 (PD‐L1 and PD‐L2); Gal‐9: galectin‐9; BAT‐3: HLA‐B associated transcript 3; Gal‐3: Galectin‐3; α‐syn: Alpha‐synuclein; FGL‐1: Fibrinogen like 1.