Cross-Talk Between Tumor Cells Undergoing Epithelial to Mesenchymal Transition and Natural Killer Cells in Tumor Microenvironment in Colorectal Cancer

Abstract

Tumor cells undergoing epithelial to mesenchymal transition (EMT) and immune cells in tumor microenvironment (TME) reciprocally influence each other. Immune cells, by supplying TME with bioactive molecules including cytokines, chemokines, enzymes, metabolites, and by physical interactions with tumor cells via their receptors, represent an important factor that affects EMT. Chronical inflammation in TME favorizes tumor growth and invasiveness and stimulates synthesis of EMT promoting transcription factors. Natural killer (NK) cells, owing to their unique ability to exert cytotoxic function independent of major histocompatibility (MHC)-mediated antigen presentation, play a significant role in the control of metastasis in colorectal cancer (CRC). Although, the cross-talk between immune cells and tumor cells in general favors the induction of EMT and inhibition of antitumor immune responses, there are some changes in the immunogenicity of tumor cells during EMT of CRC cells that increase their susceptibility to NK cell cytotoxic lysis. However, suppressive TME downmodulates the expression of activating NK cell receptors, decreases the expression of activating and increases the expression of inhibitory NK cell ligands on tumor cells, and impairs NK cell metabolism that altogether negatively affects the overall NK cell function. Furthermore, process of EMT is often associated with increased expression of programmed cell death ligand (PD-L) and expression of immune checkpoint molecules PD-1, TIGIT, and TIM3 on functionally exhausted NK cells in TME in CRC. In this review we discuss modalities of cross-talk between tumor cells and NK cells, with regard of EMT-driven changes.

Wip1 suppresses angiogenesis through the STAT3-VEGF signalling pathway in serous ovarian cancer

“…Both inflammation and EMT are correlated with tumour aggressiveness and poor prognosis in cancer patients. Inflammatory cytokines can activate transcription factors that drive EMT [ 18 , 19 ]. In our previous study, we identified that Wip1 suppresses metastasis in ovarian cancer through AKT/snail-mediated EMT.…”

The Role of Inflammatory Cytokines in the Pathogenesis of Colorectal Carcinoma—Recent Findings and Review

“…In the presence of DNA damage response failure, mismatch repair defects, and oncogene-induced replication stress, the coexistent inflammatory process can exacerbate the genetic burden and accelerate tumorigenesis through NF-κB-mediated cytokine production [ 9 ]. The semi-local inflammation promotes the accumulation of chemokines, immune cells, stromal cells, and extracellular matrix proteins, which under favorable conditions provide the foundation for the development of the tumor-supportive microenvironment [ 36 ].…”

“…TIME is composed mostly of myeloid-derived stem cells and regulatory T cells, which mediate local immunosuppression, and cytotoxic T lymphocytes (CTLs), Th2 cells, and macrophages M2, which possess very restricted antitumor activity [ 41 , 42 ]. During the progression of the disease, cancer cells change the properties of surrounding cells, forcing them to produce growth factors and proinflammatory cytokines, such as TNF-α, IL-1β, and TGF-β, that accelerate the acquisition of a mesenchymal-like phenotype during EMT [ 36 ].…”

“…While EMT can occur during wound healing or fibrosis, it is also assumed to be a key player in cancer. As a result of cancer–stromal crosstalk, stationary epithelial cells lose the intracellular adhesive properties, gain spindle cell-like mobility, and become able to migrate from primary tumors [ 36 ].…”

CAR T Cells Targeting Membrane-Bound Hsp70 on Tumor Cells Mimic Hsp70-Primed NK Cells

“…Stress-induced signals on tumor cells can trigger NK cell activity and cytotoxicity. However, in late stage cancers, the capacity of NK cells to control tumor growth can be impaired either by antigen loss or a down regulated expression of activatory receptors induced by an immunosuppressive TME ( 24 , 25 ). An ex vivo stimulation of NK cells under optimal culture conditions up-regulates the expression of activating receptors (e.g., C-type lectin receptors, natural cytotoxicity receptors, NCRs) and thereby promotes anti-tumor immunity ( 26 , 27 ).…”