NK Cell Signature Associated with Favorable Prognosis in Breast Cancer

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Tumor cell recognition by natural killer (NK) cells is mediated by the interaction of activating and inhibitory NK cell receptors with ligands expressed on the tumor cells. NK cells also express adhesion molecules that facilitate formation of the immune synapse with tumor targets. Maria Libera Ascierto (PhD student) and colleagues from the National Institutes of Health in Bethesda, Maryland, investigated whether the expression of NK-activating receptors and adhesion molecules could provide a signature to differentiate relapse and relapse-free outcomes in breast cancer.1

Relapse-free Survival Predicted

Gene-expression profiling and real time, reverse transcription polymerase chain reaction screening were performed on RNA extracted from primary breast tumor samples obtained from patients experiencing either 5 to 9 year relapse-free survival or relapse within 1 to 6 years following initial treatment. Tumors derived from patients with a favorable prognosis were characterized by increased expression of genes involved in the NK cell interaction with tumor cells and its activation signaling. In particular, upregulation of natural cytotoxicity receptors, DNAM-1 (CD226), and CD96 was observed in relapse-free patients.

Powerful Predictive Tool?

As stated by the investigators, the findings indicate that expression of the NK-activating receptors and relevant adhesion molecules involved in NK cell-target interactions can predict relapse-free survival in patients with breast cancer. Together with observations in their prior studies, the findings also highlight the effector cooperation between the innate and adaptive immune components within the tumor microenvironment. In prior studies, these investigators observed that prognostic B-cell and T-cell signatures also differentiate more favorable and poorer prognosis; these findings suggest that the presence of specific T-cell and B-cell markers identifies patients with improved prognosis.

In particular, the expression of interferon-stimulated genes and immune effectors commonly observed during the inflammatory response to pathogens, as well as genes involved in B-cell development, autoimmune reactions, and the antigen presentation pathway, were exclusively upregulated in patients with longer relapse-free survival. Among the extended signatures identified, a 5-gene signature based on expression of IGKC, GBP1, STAT1, IGLL5, and OCLN that is distinct from the FDA-cleared 70-gene signature MammaPrint panel and the Oncotype DX recurrence score assay panel was found to predict relapse-free survival with greater than 85% accuracy.

As stated by Dr. Ascierto, “Taken together, these observations describe a cancer phenotype similar to acute inflammatory processes, characterized by the presence of innate and adaptive T cell responses that favor an immune effector mechanism capable of inducing spontaneous or treatment-related cancer regression.” She further noted, “The NK-cell parameters identified in this study, together with the prognostic B-cell and T-cell signatures previously reported by us, support an association between an ‘immune response’ signature and improved outcomes in breast cancer. This ‘immune signature’ may represent a new and powerful tool for predicting breast cancer outcome that might be easily introduced in clinical practice to join other currently used predictive parameters and markers.” ■

Disclosure: Dr. Ascierto reported no potential conflicts of interest.


1. Ascierto ML, Idowu MO, Zhao Y, et al: Involvement of NK cell molecular signatures in favorable prognosis of breast cancer patients. 2012 ASCO Annual Meeting, Abstract 10565. Presented June 4, 2012.