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Published on: April 21, 2015
TNF-α deficiency underlies NK cell dysfunction in colorectal cancer
Silvia Ruggeri1, Beatrice Pizzitola1, Mattia Laffranchi1,2
1Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
Abstract:
Natural killer (NK) cells are central to innate antitumor immunity, yet their function is systemically compromised in colorectal cancer (CRC). We show that CRC patients exhibit early and pronounced alterations in peripheral blood NK cells, marked by a reduced frequency of total CD56⁺ cells, a shift toward the CD56lowCD16⁺ subset, and impaired cytotoxic and cytokine responses. Notably, plasma from CRC patients, particularly those with advanced disease, induces similar dysfunctions in healthy donor (HD) NK cells, suppressing mTORC1 signalling and effector activity. Transcriptomic profiling of HD NK cells exposed to CRC plasma revealed downregulation of TNF-α signalling components, concordant with reduced systemic and intracellular TNF-α levels in patients. Additionally, CRC plasma suppressed the JAK-STAT pathway and upregulated SOCS family genes, further dampening NK cell responsiveness. Inhibition of TNF-α in HD NK cells recapitulated the CRC plasma-induced defects, while exogenous TNF-α partially restored NK cell function, including STAT5 and S6 phosphorylation. These findings uncover TNF-α signalling deficiency as a systemic mechanism of NK cell suppression in CRC, linking impaired metabolism to immune evasion. Targeting this axis may offer a novel strategy to reinvigorate NK cell-mediated antitumor immunity in CRC.
Insights
Colorectal cancer (CRC) impairs natural killer (NK) cell immunity by reducing their frequency and function. A deficiency in TNF-α signaling, exacerbated by CRC plasma, is a key mechanism driving this suppression.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Natural killer (NK) cells are crucial for innate antitumor immunity.
- NK cell function is often compromised in colorectal cancer (CRC) patients.
Purpose of the Study:
- To investigate the mechanisms of NK cell dysfunction in CRC.
- To identify systemic factors contributing to impaired NK cell activity in CRC patients.
Main Methods:
- Analysis of peripheral blood NK cell subsets (CD56+, CD56lowCD16+) in CRC patients and healthy donors (HD).
- Incubation of HD NK cells with CRC patient plasma to assess functional and signaling changes.
- Transcriptomic profiling of NK cells exposed to CRC plasma.
- Investigating the role of TNF-α signaling via inhibition and exogenous administration.
Main Results:
- CRC patients show reduced total CD56+ NK cells, a shift to CD56lowCD16+ subset, and impaired cytotoxic/cytokine responses.
- CRC plasma induces NK cell dysfunction in HD, suppressing mTORC1 and effector activity.
- Transcriptomics revealed downregulated TNF-α and JAK-STAT signaling, with upregulated SOCS genes in NK cells exposed to CRC plasma.
- TNF-α deficiency recapitulated CRC plasma-induced defects, while TNF-α supplementation partially restored NK cell function.
Conclusions:
- TNF-α signaling deficiency is a systemic mechanism suppressing NK cell function in CRC.
- Impaired NK cell metabolism and function in CRC contribute to immune evasion.
- Targeting the TNF-α axis could be a therapeutic strategy to enhance NK cell-mediated antitumor immunity in CRC.
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