Homozygosity for Killer Immunoglobin-like Receptor (KIR) Haplotype a Is Associated to Negative Interim Positron Emission Tomography (PET) and a Favourable Outcome in Hodgkin Lymphoma

Hodgkin’s lymphoma (HL) represents an interesting model for the study of genetic and immunogenetic factors that may influence the pathogenesis of oncohematological disease and response to treatment. Natural killer (NK) cells represent a key component of the innate immune system against cancer. Their activity is modulated by the interaction between inhibitory and activating killer immunoglobin-like receptors (KIR) and their ligands. In the management of HL, Positron Emission Tomography (PET) is a standard procedure for staging of the disease. Moreover interim PET, carried out after 2 cycles (PET-2) of treatment with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD), is currently used in clinical practice as a strong predictor of response to therapy. In this study we investigated the frequencies of KIRs and their ligands in a cohort of HL patients and healthy controls. Moreover, we evaluated whether specific KIR genes or KIR haplotypes could be related to negative interim PET (PET-2) and progression-free survival (PFS).

We compared KIR genes, KIR haplotypes, HLA class I ligands and KIR-ligand combinations in a cohort of 80 HL patients (35 males/45 females, mean age 33 years) and a group of 121 healthy controls. Frequencies of activating and inhibitory KIR genes, KIR genotypes, HLA genotypes and KIR-ligand combinations were compared in HL patients and healthy controls as well as HL patients who achieved negative interim PET and those who did not. Moreover, patients were stratified into two groups according to homozygosity for KIR haplotype A (KIR genotype AA) and heterozygosity or homozygosity for KIR haplotype B (KIR genotype Bx). Multivariate analysis was performed using a binary logistic regression model, where negative interim PET was considered a dependent variable. The probability of achieving PFS according to KIR genotypes AA or Bx was calculated using the Kaplan-Meier method.

In comparison with healthy controls, HL patients had higher frequencies of inhibitory KIR genes (p=0.01) and lower frequencies of activating KIR genes (p=0.04). In the cohort of HL patients, 5-year overall survival and PFS were 91.9 and 79.4%, respectively. In multivariate analysis, homozygosity for KIR haplotype A was the only significant predictive factor of interim PET (PET-2) negativity (p=0.035). Also PFS was higher, albeit not statistically significant, in patients homozygous for KIR haplotype A (87% vs 76.6%). This lack of significance was not surprising since patients with positive interim PET were switched to a more aggressive treatment regimen with escalated BEACOPP.

In anthropological studies, it has been demonstrated that KIR haplotype A confers a better immunological response to infections in the general population. This could be the key to interpreting the association found in our study between KIR genotype AA and better response to treatment. The identification of other immunogenetic markers of high risk HL and/or response to treatment within the KIR gene system could help adapt therapeutic strategies and consent the use of novel targeted monoclonal anti-inhibitory KIR antibodies capable of modulating NK cell function.