Does natural killer (NK) cell activity correlate with cancer risk?

NK Cell Activity and Cancer Risk

Yes, NK cell activity inversely correlates with cancer risk—lower NK cell function is associated with increased cancer development and progression, while preserved or enhanced NK cell activity correlates with better outcomes and reduced malignancy risk. 1

Evidence for the Correlation

NK Cells as Critical Anti-Tumor Effectors

NK cells function as frontline defenders in cancer immunosurveillance, recognizing and destroying malignant cells without requiring prior antigen sensitization. 1, 2 Their cytotoxic capacity and interferon-γ production are essential components of direct anti-tumor responses. 1

The relationship between NK cell dysfunction and tumor burden is bidirectional and progressive:

• As circulating tumor burden increases, NK cell functions—including cellular cytotoxicity and IFN-γ production—become increasingly impaired. 1
• An inverse correlation exists between tumor burden and NK cell activation status, with diminishing expression of activation markers CD69 and CD25, plus decreased intracellular IFN-γ. 1
• This decline in NK cell function can lead to further acceleration of malignant cell growth, creating a vicious cycle. 1

Prognostic Significance

Low NK cell activity serves as an unfavorable prognostic variable across multiple cancer types:

• In patients with advanced solid tumors, NK activity is frequently reduced and correlates with worse outcomes. 3
• Disease-free patients with high peripheral blood NK activity demonstrate significantly longer metastasis-free survival compared to those with low NK activity (p < 0.026). 3
• In acute myelogenous leukemia, peripheral blood, splenic, and bone marrow NK activity are all decreased. 3

Mechanisms of NK Cell Dysfunction in Cancer

The tumor microenvironment actively suppresses NK cell function through multiple mechanisms:

• Tumor-derived cytokines (IL-1, IL-6, TNF-α) create an immunosuppressive milieu that impairs NK cell activation. 1
• Imbalance between activating and inhibitory receptors on NK cells allows tumor cells to escape immune surveillance. 4, 5
• Abnormal binding of NK cell receptors to their ligands on tumor cells prevents effective target recognition. 4, 6
• Cross-talk between tumor cells and surrounding immune cells further dampens NK cell activity. 4, 5
• Regulatory T cells and tumor-associated macrophages in the tumor microenvironment produce IL-10 and TGF-β, which exert profound suppressive effects on NK cells. 1

Clinical Implications

Monitoring Recommendations

Guidelines recommend monitoring NK cell functional assays (cytotoxicity, cytokine production) rather than absolute NK cell counts in patients with malignancies to guide prognosis and therapy. 7 Flow cytometry-based assessment of NK cell activation markers (CD69, intracellular IFN-γ) provides objective measurement of functional status. 8, 7

Therapeutic Considerations

Therapeutic strategies that enhance NK cell activity are recommended to improve anti-tumor immunity:

• Checkpoint inhibitors that restore NK cell function 1, 7
• Engineered NK cells with enhanced cytotoxic capacity 7, 5
• Antibody-dependent cellular cytotoxicity (ADCC)-based therapies 7, 6
• IL-2 activation of NK cells to restore cytotoxic function 3

Important Caveats

Factors that further suppress NK cell activity must be avoided or mitigated:

• Volatile anesthetics (isoflurane, sevoflurane) suppress NK cell cytotoxicity and cytokine production, with effects persisting for several days post-operatively. 1
• Baseline corticosteroid use may decrease NK cell-mediated anti-tumor responses. 1
• Chronic inflammation and systemic inflammatory markers correlate with NK cell dysfunction and poor cancer outcomes. 1

The evidence consistently demonstrates that NK cell activity is not merely a marker of cancer presence but an active determinant of cancer risk, progression, and outcomes. 1, 4, 5, 3, 2