KIR–HLA combinations that result in strong activation correlate with increased risk for cervical cancer.

Certain combinations of HLA class I genes and natural killer (NK) cell receptors increase the risk of developing cervical cancer, according to a study by Carrington and colleagues on page 1069. Women who possess HLA alleles that engage inhibitory NK cell receptors were less likely to develop cervical cancer, suggesting that NK cell activation may promote cancer development.

Most cervical cancers (>95%) are associated with human papillomavirus (HPV), which establishes chronic infections in the genital tract. HPV infections that do not result in cancer may be due to effective cellular immune responses that limit HPV replication. NK cells are found in HPV-positive cervical lesions and may help protect against the virus.

NK cell activation hinges on a balance between activating and inhibitory signals generated in part by a diverse group of NK cell receptors—killer cell immunoglobulin-like receptors (KIRs)—that bind HLA class I molecules on interacting cells. Combinations of KIR and HLA genes that promote either NK cell activation or inhibition have been associated with increased susceptibility to various viral and autoimmune diseases.Carrington and colleagues found that individuals whose HLA molecules primarily bound to inhibitory KIRs had a decreased risk for cervical cancer; those with certain activating HLA-KIR combinations had increased risk. NK cell activation may contribute to local inflammation, suggests Carrington, which has been associated with the progression of other types of cancer, including gastric and prostate cancer. But how NK cell activation might promote transformation remains unknown.