Induction of an inflammatory response within the cervix following human papillomavirus (HPV) infection might lead to an increased risk of cervical cancer — this is the conclusion of a new study by Mary Carrington and colleagues. Natural killer (NK) cells are an important component of the innate immune response against viruses and tumours, and their activation is thought to depend partly on the balance between inhibitory and activating receptors such as the killer immunoglobulin-like receptors (KIRs). KIRs engage specific human leukocyte antigen (HLA) class I proteins on target cells, and the considerable range of possible KIR and HLA haplotypes means that there is huge scope for variation in KIR–HLA interactions. Carrington et al. show that certain combinations of KIRs and HLA class I proteins are associated with a higher risk of developing cervical cancer.

The authors began by examining the frequencies of HLA class I alleles among people with and without cervical cancer. They found that some HLA allelic groups that are known to be high-affinity ligands for inhibitory KIRs — HLA Cw group 2 and HLA Bw4 alleles — are associated with a reduced risk of the disease.

They also found that some activating KIRs — such as KIR3DS1 — are expressed at a higher frequency by people who have cervical cancer than people who do not. Furthermore, when the authors examined the effects of KIR3DS1 together with HLA Cw group 2 and Bw4 alleles, they found a gradient of susceptibility to cervical cancer.

However, protection against cervical cancer does not come without a cost — resistance against one disease can confer susceptibility to another. Combinations of KIR and HLA genes that promote NK activation are already known to be linked to increased resistance against viral diseases, but epidemiological data show that KIR/HLA genotypes associated with viral protection are also associated with susceptibility to autoimmune diseases.

Carrington and colleagues point out that lesions in women with oncogenic HPV are often associated with concomitant inflammation of the cervix, and they suggest that NK activation might promote cancer development by contributing to local inflammation. However, although inflammation has been associated with some other cancers, further studies are needed to clarify the relationship between inflammation, transformation and the role of NK cells.