2. Negative regulator of immune system and cancer

The failure of the immune system to completely eliminate the tumor cells results in the selection of tumor cell variants that are able to resist, avoid, or suppress the antitumor immune response, leading to the escape phase [5]. The escape phase of cancer immunoediting process is activated by the simultaneous alteration of both tumor intrinsic mechanisms enabling them to hide from immune attack to avoid recognition and extrinsic mechanisms that rely on disabling or eliminating immune attack by creating suppressive environment [1, 2]. The mechanisms, at the level of tumor, that evades immunity includes the loss of tumor antigen expression, downregulation of antigen presentation through major histocompatibility complex (MHC), defects in IFN-γ receptor signaling pathway, upregulation of antiapoptotic molecules (e.g., Bcl-XL, FLIP), expression of inhibitory cell surface molecules (e.g., PD-L1, FasL), and secretion of various tumor-derived soluble factors that encourage tumor outgrowth [1, 2]. The extrinsic factor of tumor immune escape mechanism is generated by the interferences of the progressing tumor with the host immune system through the induction and/or recruitment of potent immunosuppressive cells in tumor microenvironment that ultimately hinder the induction of protective antitumor immune activity [2]. In recent years, such immune cells have gained special attention, possibly due to their ubiquitous appearance and clear association with disease progression.

Despite being considered as a major weapon of antitumor immunity, the activation, phenotype, and optimal function of T cells are regulated by a complex immunosuppressive network of tumor microenvironment [6]. Due to the weak immunogenic nature of tumor antigen, most of the tumor-specific T cells are deleted in thymic selection, resulting in low frequency of T cells with a low TCR affinity [3]. Furthermore, the presence of immunosuppressive cells in the tumor site often renders insufficient priming and boosting of T cells [3]. Over past decades, evidence implicated the fact that tumor microenvironment is dominated by Th2-type immune response than homeostatic tissue where Th1 type is prominent. Th1-type immunity promotes the expression of type 1 cytokines (TNFα, IFN-γ, and IL-2) and activates cell-mediated responses that are antitumor in nature [7]. On the other hand, Th2-type microenvironment favors the expression of type 2 cytokines (IL-4, IL-10, and TGF-β) that initiate tissue remodeling, angiogenesis, and occasional humoral immunity fostering a protumorigenic state [8]. The Th2 programming in the tumor microenvironment can be attributed by the presence of various immunosuppressive cells notably tumor-associated macrophages (TAMs), regulatory T cells (Tregs), and immature myeloid cells including the myeloid-derived suppressor cells (MDSCs) and immature dendritic cells (iDCs) that form an inhibitory network which suppresses local immunity [3]. Thus strategies involving the inhibition or subversion of suppressive immune population in tumor microenvironment hold the premise to effectively blunt Th2 programming and thereby, tilt the balance back toward Th1-based immune programs that would eventually impede tumorigenesis.

#### 2.1. Tumor-associated macrophages (TAMs) and cancer

malignant tumor quite often possess a blunt immune system [2]. Thus the immune system has an impact in the progression and severity of the disease. For most of advanced malignancies where chemotherapy is considered the treatment modality of choice often rely on the strategy to target and destroy rapidly dividing cancer cells, neglecting the possibility that immune system may contribute to the efficacy of treatment. In recent years, extensive research in the context of cancer immune system has led to the development of cancer immunotherapy field that may prove to be a powerful weapon in the treatment of cancer through modulating the immune system. The suppressive roles played by immune cells of tumor microenvironment in promoting tumor progression indicate that these cells can serve as novel therapeutic targets in the treatment of cancer [3]. Emerging evidence in recent time indicates that metal chelates of Schiff base can be used as a potent anticancer agent that imparts their cytotoxic effect through generation of reactive oxygen species (ROS) in cancer cells [4]. Recent study also highlights the role of those metal chelates as immune-stimulating agents [4] that possess the ability to inhibit or subvert immunosuppressive phenotype toward proimmunogenic type and thus associated with tumor regression. In search of novel immune-stimulatory or modulatory agents, we had synthesized a number of metal chelates of a Schiff base namely N-(2-hydroxy acetophenone) glycinate (NG). Among these, copper and manganese complexes of NG, e.g., copper N-(2 hydroxy acetophenone) glycinate (CuNG) and manganese N-(2-hydroxy acetophenone) glycinate (MnNG) exhibit immunomodulatory properties [4]. Other such metal chelates of iron, nickel, and zinc formed with the same organic moiety (NG) lack the property of immunomodulation [4]. This chapter deals with the major negative regulator of immune system during cancer, as well as the key aspects of how the immune system can be controlled or manipulated

170 Anti-cancer Drugs - Nature, Synthesis and Cell

by the application of novel Schiff base metal chelates to enhance anticancer immunity.

The failure of the immune system to completely eliminate the tumor cells results in the selection of tumor cell variants that are able to resist, avoid, or suppress the antitumor immune response, leading to the escape phase [5]. The escape phase of cancer immunoediting process is activated by the simultaneous alteration of both tumor intrinsic mechanisms enabling them to hide from immune attack to avoid recognition and extrinsic mechanisms that rely on disabling or eliminating immune attack by creating suppressive environment [1, 2]. The mechanisms, at the level of tumor, that evades immunity includes the loss of tumor antigen expression, downregulation of antigen presentation through major histocompatibility complex (MHC), defects in IFN-γ receptor signaling pathway, upregulation of antiapoptotic molecules (e.g., Bcl-XL, FLIP), expression of inhibitory cell surface molecules (e.g., PD-L1, FasL), and secretion of various tumor-derived soluble factors that encourage tumor outgrowth [1, 2]. The extrinsic factor of tumor immune escape mechanism is generated by the interferences of the progressing tumor with the host immune system through the induction and/or recruitment of potent immunosuppressive cells in tumor microenvironment that ultimately hinder the induction of protective antitumor immune activity [2]. In recent years, such immune cells have gained special attention, possibly due to their ubiquitous appearance and clear association with disease progression.

2. Negative regulator of immune system and cancer

Macrophages are well distributed innate immune cells, known for their versatility and plasticity by exerting different functional properties in response to diverse environment stimuli. Originating from blood monocytes, macrophages are recruited into peripheral tissue where they differentiate into distinct mature macrophages by the expression of particular markers [9]. In mice, macrophages are known to exhibit phagocytic activity and express CD11b, F4/80, and colonystimulating factor-1 receptor (CSF-1R; CD115) marker [9]. In humans, phagocytosis, CD68, CD163, CD16, CD312, and CD115 are the major characteristic features of this lineage [9]. Diverse immunological signals in tumor microenvironment lead macrophages to undergo polarized activation [10]. Such a polarization includes the "activated" macrophage (M1 macrophages) and "alternatively activated" macrophages (M2 macrophages). M1 macrophages that are activated following stimulation with Th1 cytokine IFN-γ alone or in combination with LPS or TNF-α or through engagement of Toll-like receptors (TLRs) are characterized by elevated expression of class II major histocompatibility complex (MHC), expression of interleukin (IL-12) and tumor necrosis factor α (TNF-α), generation of reactive oxygen species and nitric oxide (NO), and the ability to kill pathogens and cells [11]. Early in tumorigenesis M1 macrophages, generally characterized by an IL-12high IL-10low phenotype, support immune response to the nascent tumor by the secretion of large amounts of IL-12, IL-1α, IL-1β, IL-6, and TNF-α, and IFN-γ by Th1 lymphocytes. Furthermore, the induction of nitric oxide (NO) and ARG1 expression by M1 macrophages increases CTL cytotoxicity on tumor cells. In contrast, the "alternatively activated" macrophages (M2 macrophages) that differentiate in response to IL-4, IL-13, M-CSF/CSF-1, IL-10, and TGF-β1 are associated with inducing Th2-type responses, including humoral immunity and wound healing [11]. Interestingly in the context of tumor immune response, reports highlights that macrophages in tumor microenvironment are biased away from the M1 to M2 type macrophages and known as tumor-associated macrophages (TAMs) [12]. During late-stage tumor progression, TAMs exhibit an IL-12low IL-10high phenotype with low tumoricidal activity [12] in TME. Growing body of literature has well established the fact that TAMs have been known to provide a favorable microenvironment for tumor growth, tumor survival, and angiogenesis [11].
