Cytokine- and chemokine-induced inflammatory colorectal tumor microenvironment: Emerging avenue for targeted therapy

Abstract

Colorectal cancer (CRC) is a predominant life-threatening cancer, with liver and peritoneal metastases as the primary causes of death. Intestinal inflammation, a known CRC risk factor, nurtures a local inflammatory environment enriched with tumor cells, endothelial cells, immune cells, cancer-associated fibroblasts, immunosuppressive cells, and secretory growth factors. The complex interactions of aberrantly expressed cytokines, chemokines, growth factors, and matrix-remodeling enzymes promote CRC pathogenesis and evoke systemic responses that affect disease outcomes. Mounting evidence suggests that these cytokines and chemokines play a role in the progression of CRC through immunosuppression and modulation of the tumor microenvironment, which is partly achieved by the recruitment of immunosuppressive cells. These cells impart features such as cancer stem cell-like properties, drug resistance, invasion, and formation of the premetastatic niche in distant organs, promoting metastasis and aggressive CRC growth. A deeper understanding of the cytokine- and chemokine-mediated signaling networks that link tumor progression and metastasis will provide insights into the mechanistic details of disease aggressiveness and facilitate the development of novel therapeutics for CRC. Here, we summarized the current knowledge of cytokine- and chemokine-mediated crosstalk in the inflammatory tumor microenvironment, which drives immunosuppression, resistance to therapeutics, and metastasis during CRC progression. We also outlined the potential of this crosstalk as a novel therapeutic target for CRC. The major cytokine/chemokine pathways involved in cancer immunotherapy are also discussed in this review.

Keywords: chemokine; colorectal cancer; cytokine; drug resistance; epithelial-mesenchymal transition; immunosuppression; immunotherapy; inflammation; metastasis; tumor microenvironment.

FIGURE 1

Expression profile of cytokines and chemokines in CRC. Differentially expressed cytokines comparing normal solid tissues (blue color) with primary tumors (red color) of COADREAD. Expression data of normal and cancer tissues for TCGA or GDC was downloaded from University of California, Santa Cruz (UCSC) Xena (https://xenabrowser.net/) genomics explorer. A total of 431 samples data of COADREAD was available for comparison, including 380 tumors and 51 normal solid tissues. Boxplots were created, and expression values were log‐transformed for presentation and comparison. P values were assessed using Mann‐Whitney U Test. *P < 0.05; **P <0.01; ***P <0.001. Abbreviations: CRC, colorectal cancer; TCGA, The Cancer Genome Atlas; COADREAD, Colorectal adenocarcinoma Rectal adenocarcinoma; GDC, Genomic Data Commons; CSF, colony‐stimulating factor 2; IFG, interferon gamma; IL, interleukin; TGF, tumor growth factor; TNF, tumor necrosis factor; VEGFA, vascular endothelial growth factor A; FPKM, fragments per kilobase of transcript per million mapped reads

FIGURE 2

Cytokines and chemokines as inducers of inflammation. Different immune components, including Th1 cells, M1 macrophages, Th2 lymphocytes, Th17 lymphocytes, CAFs, plasma cells, and neutrophils, are involved in inflammation in CRC by secreting different interleukins and chemokines. However, M2 macrophages oppose this inflammation. The collective interplay of these cytokines determines the inflammatory microenvironment in CRC, which leads to increased ROS‐ and other inflammatory radical‐mediated DNA damage and mutagenesis in CRC. Abbreviations: CRC, colorectal cancer; CAFs, cancer‐associated fibroblasts; Th, T helper cells; ROS, reactive oxygen species

FIGURE 3

Cytokines and chemokines as modulators of the TME. Different immune cell types, such as neutrophils, T‐cell subtypes, macrophages, CAFs, and innate lymphoid cells, play distinct roles in the secretion of different interleukins, contributing to the activation of inflammatory NF‐κB, proliferative STAT3/MAPK/AKT, and proangiogenic VEGF and SNAI1, which induces EMT. The different chemokine receptor‐ligand pairs support CRC cell metastasis in the liver, whereas some interleukins (IL‐15 and IL‐12) inhibit metastasis and act as antitumor cytokines. Abbreviations: CAFs, cancer‐associated fibroblasts; NF‐κB, nuclear factor kappa B; VEGF, vascular endothelial growth factor; EMT, epithelial to mesenchymal transition; CRC, colorectal cancer; SNAIl, snail family transcriptional repressor 1; IL, interleukin; STAT3/MAPK/AKT, signal transducer and activator of transcription 3/ mitogen‐activated protein kinase/protein kinase B

FIGURE 4

The complex network in the TME orchestrates EMT. CRC stromal cells such as Tregs, TAMs, MDSCs, CAFs, and neutrophils secrete various cytokines and chemokines into the surrounding environment. These soluble factors activate diverse signaling pathways, including Ras/Raf/ERK, PI3K/AKT, TGF/SMAD, JAK/STAT, Integrin/FAK, and Wnt/GSK/β‐catenin. Activation of these signaling pathways induces EMT in CRC cells by promoting a transcriptional program that downregulates E‐cadherin and upregulates N‐cadherin, vimentin, fibronectin, and FSP1. Integrin/FAK signaling pathway activation induces cytoskeleton reorganization, a prerequisite for invasion and metastasis. Abbreviations: Tregs, regulatory T cells; TAMs, tumor‐associated macrophages; MDSCs, myeloid‐derived suppressor cells; CAFs, cancer‐associated fibroblasts; EMT, epithelial to mesenchymal transition; CRC, colorectal cancer; FSP1, ferroptosis suppressor protein 1; Ras/Raf/ERK, rat sarcoma virus/ rapidly accelerated fibrosarcoma/ extracellular signal‐regulated kinases; PI3K/AKT, phosphoinositide 3‐kinases/ protein kinase B; TGF/SMAD, transforming growth factor/ mothers against decapentaplegic homolog 1; JAK/STAT, Janus kinase‐signal transducer and activator of transcription

FIGURE 5

Cytokine‐ and chemokine‐mediated immunosuppression promotes CRC metastasis. Blunting antitumor immunity involves induction of regulatory DCs and CD4+ T cells and inhibition of circulating and tumor‐infiltrating CTLs through MDSCs (via RNS, IL‐10, IFN‐γ, PD‐L1, and IDO) and EMT‐exhibiting tumor cells (via TSP‐1). Tumor‐born cytokines trigger inflammation to interrupt myelopoiesis, yielding MDSCs that chemotactically reach the peritoneum or liver. RNS species also subvert immunotherapy by nitrating the TCR and CD16 to prohibit tumor‐directed cytotoxicity from NK/T cells. MDSCs mediate local invasion by MMP‐9 production. Tumor cells and TAMs direct circulating MDSCs to localize in the liver to forge the hepatic PMN needed for promoting LM. The most likely chemo‐attractants responsible for metastasis include IL‐6 from CRC cells exhibiting S1PR1‐STAT3 signaling and CXCL1 (in circulation or from premetastatic liver) from VEGFR‐engaged TAMs in the CRC TME. Abbreviations: CRC, colorectal cancer; DCs, dendritic cells; CTLs, cytotoxic T cells; MDSCs, myeloid‐derived suppressor cells; RNS, reactive nitrogen species; EMT, epithelial to mesenchymal transition; IL‐10, interleukin‐10; IFN‐γ, interferon gamma; PD‐L1, programmed death‐ligand 1; IDO, indoleamine‐pyrrole 2,3‐dioxygenase; TCR, T cell receptor; MMP9, matrix metalloproteinase 9; NK/T, natural killer/T; PMN, polymorphonuclear neutrophils; LM, liver metastasis; TAMs, tumor‐associated macrophages; IL‐6, interleukin‐6; S1PR1, sphingosine‐1‐phosphate receptor 1; STAT3, signal transducer and activator of transcription 3; CXCL1, C‐X‐C motif chemokine ligand 1; VEGF‐R, vascular endothelial growth factor‐receptor; TME, tumor microenvironment; CD16, cluster of differentiation 16