The Expression of Immune Checkpoint Receptors and Ligands in the Colorectal Cancer Tumor Microenvironment

Colorectal cancer (CRC) is the third most common malignancy and the second most common cause of cancer-related mortality worldwide. A total of 20% of CRC patients present with distant metastases, most frequently to the liver and lung. In the primary tumor, as well as at each metastatic site, the cellular components of the tumor microenvironment (TME) contribute to tumor engraftment and metastasis. These include immune cells (macrophages, neutrophils, T lymphocytes, and dendritic cells) and stromal cells (cancer-associated fibroblasts and endothelial cells). In this review, we highlight how the TME influences tumor progression and invasion at the primary site and its function in fostering metastatic niches in the liver and lungs. We also discuss emerging clinical strategies to target the CRC TME.

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TNF-alpha Induces Pro-Inflammatory Factors in Colorectal Cancer Microenvironment

Medical Science and Discovery ◽

10.36472/msd.v7i4.368 ◽

2020 ◽

Vol 7 (4) ◽

pp. 466-469

Author(s):

Ahu Pakdemirli ◽

Gizem Calibasi Kocal

Keyword(s):

Colorectal Cancer ◽

Tumor Microenvironment ◽

Cancer Cells ◽

Interleukin 6 ◽

Interleukin 8 ◽

Soluble Factors ◽

Tnf Α ◽

Colorectal Cancer Cells ◽

Cancer Tumor ◽

Cellular Components

Objective: The tumor microenvironment has a crucial role in organizing cancer malignancy, progression, drug resistance and survival. It consists of cellular and non-cellular components. These non-cellular components such as cytokines, extracellular matrix, growth factors and metabolites are responsible for shifting the action from pro-cancer to anti-cancer effects. Twenty percent of all cancers occur in association with chronic inflammation via cytokines. Even cancers that are not caused by chronic inflammation, present high levels of cytokine expression pattern in their tumor microenvironment. Tumor necrosis factor-alpha (TNF-α) and some interleukins are characterized as pro-tumorigenic cytokines and they were involved in cancer by presenting their ability to activate the oncogenic transcription factors. The aim of this study is to evaluate the remodeling of colorectal cancer tumor microenvironment by TNF-α. Material and Methods: TNF-α (5ng/ml) was applied to HT-29 colorectal cancer cells, then human soluble factors were determined by using Human Cytokine Group 1, 8 plex Panel (Bio-Rad Laboratories Inc. USA) and Magpix Luminex instrument and xPONENT software (version 4.2, Luminex Corp, Austin, Texas, US). The results were normalized to total protein concentration estimated via Bradford assay. Results: Current research highlights the effect of TNF-α on the tumor microenvironment. Interleukin-6 and interleukin -8 soluble factors were higher in TNF-α treated colorectal cancer cells when compared with untreated control group. Conclusion: The results of the study show that TNF-α is responsible for elevating the levels of interleukin-6 and interleukin-8, which are associated with inflammation in the tumor microenvironment. Key words: Colorectal Cancer, Tumor Microenvironment, Cytokines, TNF-α, Interleukin-6, interleukin -8

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Neutrophils Extracellular Traps Inhibition Improves PD-1 Blockade Immunotherapy in Colorectal Cancer

Cancers ◽

10.3390/cancers13215333 ◽

2021 ◽

Vol 13 (21) ◽

pp. 5333

Author(s):

Hongji Zhang ◽

Yu Wang ◽

Amblessed Onuma ◽

Jiayi He ◽

Han Wang ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Microenvironment ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Critical Role ◽

Dnase I ◽

Neutrophil Extracellular Trap ◽

Advanced Malignancy ◽

Extracellular Traps

Immune checkpoint inhibitors can improve the prognosis of patients with advanced malignancy; however, only a small subset of advanced colorectal cancer patients in microsatellite-instability-high or mismatch-repair-deficient colorectal cancer can benefit from immunotherapy. Unfortunately, the mechanism behind this ineffectiveness is unclear. The tumor microenvironment plays a critical role in cancer immunity, and may contribute to the inhibition of immune checkpoint inhibitors and other novel immunotherapies in patients with advanced cancer. Herein, we demonstrate that the DNase I enzyme plays a pivotal role in the degradation of NETs, significantly dampening the resistance to anti-PD-1 blockade in a mouse colorectal cancer model by attenuating tumor growth. Remarkably, DNase I decreases tumor-associated neutrophils and the formation of MC38 tumor cell-induced neutrophil extracellular trap formation in vivo. Mechanistically, the inhibition of neutrophil extracellular traps with DNase I results in the reversal of anti-PD-1 blockade resistance through increasing CD8+ T cell infiltration and cytotoxicity. These findings signify a novel approach to targeting the tumor microenvironment using DNase I alone or in combination with immune checkpoint inhibitors.

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