Skin Cancer Risk Is Modified by KIR/HLA Interactions That Influence the Activation of Natural Killer Immune Cells

Abstract

Natural killer (NK) cell phenotype is partially mediated through binding of killer immunoglobulin-like receptors (KIR) with HLA class I ligands. The KIR gene family is highly polymorphic and not well captured by standard GWAS approaches. Here we tested the hypothesis that variations in KIR gene content combined with HLA class I ligand status is associated with keratinocyte skin cancers using a population-based study of basal cell carcinoma (BCC) and squamous cell carcinomas (SCC). We conduced an interaction analysis of KIR gene content variation and HLA-B (Bw4 vs Bw6) and HLA-C (C1 vs C2). KIR centromeric B haplotype was associated with significant risk of multiple BCC tumors (OR=2.39, 95% CI: 1.10–5.21), and there was a significant interaction between HLA-C and the activating gene KIR2DS3 for BCC (pinteraction = 0.005). Furthermore, there was significant interaction between HLA-B and telomeric KIR B haplotype (containing the activating genes KIR3DS1 and KIR2DS1) as well as HLA-B and the activating KIR gene 2DS5 (pinteraction 0.001 and 0.012, respectively). Similar but greatly attenuated associations were observed for SCC. Moreover, previous in vitro models demonstrated that p53 is required for upregulation of NK ligands, and accordingly, we observed there was a strong association between the KIR B haplotype and p53 alteration in BCC tumors, with a higher likelihood that KIR B carriers harbor abnormal p53 (p<0.004). Taken together, our data suggest functional interactions between KIR and HLA modify risks of BCC and SCC, and that KIR encoded by the B genes provide selective pressure for altered p53 in BCC tumors.

Killer immunoglobulin‐like receptor repertoire analysis in a Caucasian Spanish cohort with inflammatory bowel disease

“…In this context, the activating KIR gene KIR2DS1 has also very recently been reported to have an important predictive potential for early onset of Type 1 autoimmune hepatitis . Similar findings concerning KIR2DS1 and KIR2DS5 and skin cancer risk have also recently been reported . In addition, the presence of KIR2DS5 seems to confer protection against adult immune thrombocytopenia .…”

Genotype B of Killer Cell Immunoglobulin-Like Receptor is Related with Gastric Cancer Lesions

“…In fact, it was reported that patients with metastatic colorectal cancer had complete response to FOLFIRI (5-fluorouracil, leucovorin and irinotecan) treatment when B haplotype was present 35 . Interestingly, there was a strong association between the KIR B haplotype and p53 alteration in Basal cell carcinoma tumors, with a higher likelihood that KIR B carriers harbor abnormal p53 34 .…”

“…On the other hand, activating KIR haplotypes would have opposite effects on distinct malignancies depending on whether inflammation is or is not a major component of tumor pathogenesis 33 . Although, it should be noted that an activator haplotype could also be expected to be associated with increased ability to eliminate tumors 1 , 34 . In fact, it was reported that patients with metastatic colorectal cancer had complete response to FOLFIRI (5-fluorouracil, leucovorin and irinotecan) treatment when B haplotype was present 35 .…”

“…Our work associates the risk to develop GC with the B KIR genotypes and the gene cluster included within the telomeric part. There is a need to better understand the functional role of the diversity in KIR genes content in GC, together with the participation of other factors involved in GC development, such as peptides derived from cancer that are presented by HLA class I molecules to KIR receptors 34 . Since HLA molecules are ligands of NK cells, they regulate the variation in immune responses to different antigens by selection and suppression/activation of NK cells, and have a relevant role in the combat against GC 9 , 38 .…”

P53 Transposable Elements and Regulatory Introns Inform Codondex Cell Selection for Autologous Trigger of Immune Cascade

“…F indings suggest differential Basal and Squamous cell carcinoma risk with centromeric and telomeric activating KIR, and selective pressure from this NK based inter-individual antigen variability drives p53 alteration in skin tumors 25 .…”