**3. Conclusion and future aspects**

The presence of *CCR5∆32* polymorphism was not correlated with worse response in metastatic melanoma patients undergoing adoptive therapy [39]. Conflicting studies exist on the effect of *CCR5∆32* polymorphism on immunotherapy or immunochemotherapy. Hamid et al. did not report any significant relationship between the existence of *CCR5∆32* genotype or

Natural killer (NK) cells, large granular lymphocytes, have role on the early innate immune response. In contrast to T cells, which remember foreign antigens through T-cell receptors in the context of major histocompatibility complex (MHC) molecules, NK cells are programmed to eliminate infected or transformed cells. Activation of NK cells, known as "missing-self" model due to the absence of MHC molecules depends on the numerous signals through their respective activating or inhibitory receptors [41]. The *killer immunoglobulin-like receptor (KIR)* gene encodes both activating and inhibitory NK-cell surface receptors. *HLA class I* gene encodes ligands of inhibitory KIR (HLA-C1 for KIR2DL2/3, HLA-C2 for KIR2DL1, HLABw4 for KIR3DL1), and the interaction between KIR and HLA class I ligands leads to NK inhibition. NK cells also express Fc receptors [42]. The interplay between KIR and HLA is crucial for positive outcomes of immune-related therapies. KIR/KIR-ligand mismatch is associated with improved outcome

Delgado et al. reported that KIR receptor-ligand mismatch was related with response or improvement of relapsed or refractory neuroblastoma patients receiving interleukin-2-based

There are three fragment c gamma receptor (FcγR) classes such as (i) FcgRI, capable of highaffinity binding monomeric IgG, (ii) FcgRII with low-affinity binding, and (iii) FcgRIII interaction with complexed IgG. FcgRII and FcgRIII have variants with different binding affinity

Several groups have investigated the role of *FcγR* polymorphisms in the response of monoclonal antibodies (mAbs) such as rituximab, cetuximab, and trastuzumab. A correlation was reported between FcgRIIa polymorphisms and complete response in rituximab-based regimen received by non-Hodgkin lymphoma patients [44]. In another study performed to understand the influence of the *FCGR3A* gene polymorphism on rituximab response of non-Hodgkin lymphoma patients, again a correlation was found between *FCGR3A genotype* and clinical response [45]. In a preliminary study, *FCGR2A* and *FCGR3A* polymorphisms were shown as useful markers to predict clinical outcome in metastatic colorectal cancer patients treated with cetuximab, a chimeric immunoglobulin G1 (IgG1) monoclonal antibody (mAb) against epidermal growth factor receptor (EGFR) [46]. Musolino et al. reported a correlation between *FCGR3A* and objective response rate and progression-free survival in patients with HER-2/neu-amplified breast cancer receiving trastuzumab. Also an association was determined between the combination of F*CGR2A* and *FCGR3A* and better objective response rate and progression-free survival [47]. Cheung et al. reported an association between *FcγR2A* polymorphism and progression-free survival in the response of neuroblastoma patients to the anti-GD2 antibody [48]. As a result, KIR-HLA immunogenetics can give useful information

rs1799987, c.-301 + 246A > G, polymorphism and responsiveness to ipilimumab [40].

to immune-related therapies as well as autologous stem cell transplantation [42].

treatment, consistent with a role for NK cells in this clinical response [43].

immune complexes such as FcgRIIa (131H/R) and FcgRIIIa (Val158Phe) [44].

**2.4. KIR, HLA, and Fcγ polymorphisms**

148 Genetic Diversity and Disease Susceptibility

Immunogenomics uses advance genomic analysis tools to distinguish the limitations of the immune system, and pharmacogenomics identifies the variability of pharmacologic responses based on individual's genetic/germline variations. Integration of both immunogenomics and pharmacogenomics forms immunopharmacogenomics to revolutionize the immunotherapy applications through the identification of genetic status of immunoregulatory molecules. This approach could be used to develop a better understanding for immunologic reactions, select patients for immunotherapy, and predict the side effects and response to anticancer treatment (not only immunotherapy but also chemo/radiation therapy). Although the immunopharmacogenetic applications are limited in clinical practice, it is clear that immunopharmacogenomics will become an important approach of cancer management in immunotherapy era.
