Abstract
With the unavoidable progress of genomics technologies, “one size fits all” strategy has switched to individual-specific treatment approaches. Hence pharmacogenomics-based personalized cancer medicine has emerged. Promising treatment option immunotherapy includes either “take the brakes off immune system (i.e., checkpoint blockade therapy) or the use of immune cells expanded in an in vitro tumor-free environment’’. Both options have been varied and included unpredictable results. Combination of cancer immunotherapy and pharmacogenomics applications may contribute to solve the complexity of outcome prediction and variations between individuals receiving the same immunotherapeutic treatment. To enhance the tumor immunity and determine cancer patients who response to immunotherapy, classification based on gene polymorphisms in key immunoregulatory molecules including antigen-presenting molecules, immunoglobulins and their receptors, cytokine/chemokines and their receptors, adhesion and costimulatory molecules, toll-like receptors, and intracellular signaling molecules plays a vital role in redirecting or modulating the function of immune cells. Therefore, polymorphisms in immunoregulatory molecules and their impact on immunotherapeutic outcome should be considered in cancer management.
Keywords
- cancer
- immunopharmacogenomics
- personalized immunotherapy
- polymorphisms
1. Introduction
The host immune system has a crucial role on the pathogenesis of many diseases, including cancer. Tumorigenesis depends not only on cellular biology but also on immune responses. The tumor development and progression are associated with the interaction between the immune system and malignant cells. The effect of immune responses has been counted on for both cancer immunotherapies and a broad range of cytotoxic agents as well as molecular targeted drugs. With the accumulation of information about the immune responses in tumor immune surveillance, the fame of cancer immunotherapy is increasing. Some cancer immunotherapies, such as monoclonal antibodies, cytokines, cancer vaccines, and cell-based therapies, have been developed and incorporated into clinical practice for the activation of the host immune response to eliminate cancer cells [1, 2].
2. Importance of personalized cancer therapy on immunotherapy
With characterization of alterations on immunity-related molecules through deep sequencing tools in the genomic era, immunotherapies are revolutionizing cancer treatment. Natural variations in nucleic acid sequence named as gene polymorphisms exist in general population with a high frequency and include no side effect for the people. Single nucleotide polymorphisms (SNPs) are the most common polymorphism in population [3]. SNPs can be also recognized as biological markers to identify genes that are associated with diseases. It has been displayed that some SNPs have effects on individual’s response to some drugs. Therefore research groups are focused on the investigation of how SNPs in the human genome correlate with drug response to get more successful therapy regimes in personalized medicine era [4]. At this point, immunopharmacogenomics that incorporates immunogenomics and pharmacogenomics aims to improve a better approach for how the immune system impacts to the immunotherapy response.
2.1. PD-1/PD-L1 polymorphisms
The blockade of immune checkpoints modulating immune responses has recently been emerged as an immune therapy against cancer. Different immune checkpoint molecules such as programmed cell death 1 receptor (PD-1), an immune checkpoint receptor on immune cells (especially on T lymphocytes); and programmed death-1 ligand-1 (PD-L1) on tumor cells or tumor-infiltrating immune cells, have been associated with tumor immune evasion [5]. Interaction of PD-1 with PD-L1 starts antitumor immune response suppression; therefore blockade of PD-1/PD-L1 binding has been recently applied for antitumor immune therapy [6]. PD-1 is expressed on some immune cells, including T cells, natural killer T (NKT) cells, mature CD4+ and CD8+ T cells, some dendritic cells, B cells, lymph node, and bone marrow cells [4]. PD-1 is commonly expressed immunoinhibitory receptor that belongs to CD28/B7 family, and it is expressed on some immune cells, including T cells, natural killer T (NKT) cells, mature CD4+ and CD8+ T cells, some dendritic cells, B cells, lymph node, and bone marrow cells. PD-1 has two opposite roles such as downregulation of ineffective immune responses and expansion of malignant cells by preventing of protective antitumor immune responses [7]. PD-1 has function on the inhibition of T-cell activation, production, and survival [4]. PD-L1, ligand of PD-1, is a member of the B7 family of immune-regulatory ligands. It is expressed on functioning active T cells, B cells, dendritic cells, and macrophages (antigen-presenting cells) and activates various tissue groups by inflammatory cytokines [7]. PD-L1 has two different forms as membrane bound and soluble form. Both of these forms have been found on CD28/B27 family such as CTLA-4, CD28, and B7-H4 [8].
PD-L1 has role on the negative regulation of immunological response. PD-L1 overexpression can prevent to form antitumor immune responses against cancer cells; hence increased expression of PD-L1 on tumor cells may be predictive for a blockade of the PD-L1/PD-1 binding [9]. Some studies have shown that PD-L1 is also expressed on many types of cancer cells (including melanoma, lung cancer), and it has been reported that expression of PD-L1 ligands by cancer cells results in the evasion of the immune system. They stop the production of tumor-specific T cells by propagation of inhibitory signals which cause damaged antitumor immunity [7, 10]. Based on their function on antitumor immune response suppression, PD-1 and PD-L1 can be considered as powerful biomarkers for new tumor formation or progression of cancer. In literature some studies are focused on their role on genetic susceptibility, and some of them are focused on their prognostic or predictive significance. In literature some polymorphisms on PD-1 which is encoded by
2.2. CTLA4 polymorphisms
After the determination and characterization of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) as a key negative regulator in immune response (broadly named as checkpoint molecule), studies have increased to develop cancer immunotherapy targeting this co-inhibitory molecule. CTLA-4 (CD152) is a member of immunoglobulin (Ig) superfamily and functions for downregulation of T-cell activation. CTLA-4 expressed by activated T cells binds to B7.1 (CD80) and B7.2 (CD86) on antigen-presenting cells and transmits an inhibitory signal to T cells, so it can restrict the density and extent of the immune responses. The complex formed from CTLA-4 and B7 proteins (B7.1 and B7.2) can switch activated T cells into inhibitory T cells. This change promotes tumor escape from immunosurveillance [23]. Although lymphoproliferative disorders and severe autoimmune diseases have been shown in CTLA4-knockout mice; CTLA-4 blockade can boost immune responses in tumor-transplanted mice, as well as extending antitumor immune responses and rejection of tumors [24, 25]. It has been shown that blocking of CTLA-4, namely, downregulation of T-cell activation, can lead the cancer regression in patients with different cancers due to the enhancing immune responses as well as antitumor activity [23, 26]. However, not all patients can benefit from the treatment of CTLA-4 blockade, and some of them developed severe autoimmune reactions. The mechanisms of this interindividual variability in response to immunotherapy are not well understood.
Some
2.3. CCR5 polymorphisms
Pro-inflammatory cytokines, chemokines and other protein-structured molecules are secreting from cancerous cells and their stromal environment. Chemokine family belongs to chemotactic cytokines and has 44 members. Chemokines have role in homeostasis and immunity by controlling the leukocyte trafficking and induction, so they have role in organogenesis, cell growth, and differentiation. Tumor-related chemokines have important role in cancer biology, in terms of leukocyte infiltration, angiogenesis, and immune evasion. Based on the number and spacing of conserved cysteine residues on their N-terminus, chemokines consist of four subgroups named as CX3C, CXC, CC, and C [32, 33]. Chemokines act through their interactions with specific chemokine receptors located on the cell surface. Most of the cancerous cells overexpress these specific chemokine receptors which have role together with chemokines in cellular survival, proliferation, migration, invasion, and metastasis. In humans, the chemokine receptor family includes 24 members, and they are divided into four subfamilies (CX3CR, CXCR, CCR, and CR) based on the class of chemokines that they interact. Specific ligand-receptor binding induces GDP to GTP exchange, and this activates the downstream signaling effectors for the propagation of cellular pathways [34, 35].
It is considered that chemokine receptors are promising targets for new immunotherapies since the detection of overexpressed chemokine receptors on the surface of cancer cells [36]. Systemic administration of interleukin-2 and checkpoint inhibitors increases the secretion of chemoattractants such as ligands of CCR5 and CXCR. Therefore polymorphisms on CCR5 and CXCR chemokine receptors affect the migration capability of tumor-infiltrating lymphocytes to the tumor location [37]. So response rates to immunotherapy vary among patients. Ugural et al. showed that genotypic status of CCR5 chemokine receptor has an impact on the immunotherapy (interferons or interleukin-2) responses in patients with metastatic melanoma. A strong association was determined between the
2.4. KIR, HLA, and Fcγ polymorphisms
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
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 treatment, consistent with a role for NK cells in this clinical response [43].
There are three fragment c gamma receptor (FcγR) classes such as (i) FcgRI, capable of high-affinity 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 immune complexes such as FcgRIIa (131H/R) and FcgRIIIa (Val158Phe) [44].
Several groups have investigated the role of
3. Conclusion and future aspects
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.
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