EVALUATION OF NK CELL CYTOTOXICITY BIOMARKERS OF TUMOR PROGRESSION IN BREAST CANCER

The success of cancer therapy depends not only on adequateclinical procedures that aim to eliminate tumor cells, but alsoon the functional state of the patient immune system. NK cellcytotoxicity is regulated by the interaction between killerimmunoglobulin-like receptors (KIRs) and human leukocyteantigen (HLA) class I ligands on target cells and the differentbinding affinity of the Fc?receptor IIIA (CD16A) for IgG-coated tumor cells. Thus, it is conceivable that KIR andCD16A gene contents may contribute to the function of NKcells by modulating an immune response in breast cancer(BC). BC progression and metastases have been linked toanti-tumor immune response inefficacy. Therefore, we haveinvestigated the combined effect of the KIR genes and theirHLA-C ligands together with CD16A on the susceptibilityand progression to development of BC in Italian patients andmatched controls (Ctrs). The gene polymorphisms were inves-tigated by PCR-SSP methods for typing of KIR receptors andby PCR-SBT for HLA-C and FCGR3A alleles. Our resultstyped in 47 BC pts and 39 Italian female Ctrs showed a pre-disposing effect of KIR2DS1 to more aggressive neoplasms(stage III-IV), both considering the gene alone (III-IV stage63.2% vs 0-II 32.1%, p=0.043 OR=3.619) and in theKIR2DS1/HLA-C2+ combination (42.9% vs 6.3%, p=0.030). On the contrary, the KIR2DL2 and KIR2DS4ins genes, whichare linked on the same haplotype, seemed to be protective fora more aggressive neoplasm (36.8% vs 60.7%, p=0.04; 10.5%vs 35.7% vs, p=0.06, respectively). The synergic absence ofthese two KIR genes increased the occurrence of moreadvanced BC by 5.7-fold (63.2% vs 23.1% in Ctrs P=0.0071).Regarding FCGR3A48 A/T/G and 158 G/T gene polymor-phisms, we described a higher frequency of 48T-158G and48T-158T haplotypes in both BC and Ctrs groups, eventhough the 48TT-158TT (LL/FF) genotype was presentmainly in controls (3.6% vs 11.0%). Our findings evidence apotential role of KIR-gene content together with their HLA-Cligands in BC tumoral progression, suggesting that the devel-opment of breast cancer can result from disorder of immuneregulation.