**2. Basic principles of immune response**

There has been major growth in the understanding of the immune role and its relationship to cancer progression and therapy. The immune system comprises of a multitude of intercon‐ nected cells and tissues, distributed in the body. It basically consists of three general categories of blood cells: 1) lymphocytes (T, B cells and natural killer (NK) cells); 2) myeloid cells (macrophages, dendritic cells, and antigen presenting cells); and 3) granulocytes (neutrophils, basophils, and eosinophils). Simplified, the immune system protects the organism from harmful foreign agents (antigens) by producing specific proteins (antibodies). Those antibod‐ ies circulate until they find and attach to the targeted antigen, thus triggering immune response and destruction of the antigen-containing cells.

#### **2.1. Principles of immune response in solid tumors**

The anti-cancer immune response could be largely divided into two types: innate and adaptive immune response. The innate immunity includes the granulocytes, macrophages, dendritic cells, mast cells, and NK cells serving as a first-line protective mechanism, recognizing stressed mutating cells of the organism, and triggering effector mechanism, aiming their eradication. Subsequently, the adaptive immune response is triggered - it consists of specific immune activation of B cells, CD 4- and CD 8-expressing T-lymphocytes.

#### *2.1.1. Innate antitumor response*

scientific researchers continued the struggle to understand the role of Virchow's findings, aiming to link those processes. The elucidation of such relation could give an insight into the processes of tumorigenesis, tumor growth, and metastatic spread; it could potentially provide subsequent opportunities to develop strategies to impact the diagnosis, prognosis, and eventually to improve the cancer treatment process. The synallagmatic reciprocal talk between the host immune system and the tumor has been intensively studied. The processes of the host immune control over the tumor, immunoediting by the tumor, the immune escape, and the development of immune tolerance and suppression are described in this chapter. Our aim is also 1) to highlight the principles of cancer-related immune mechanisms, immunotherapy, and their role in the process of treatment of solid tumors; - and 2) to discuss the options to combine immunotherapeutic and chemotherapeutic agents trying to overcome the mechanisms of immune or inflammatory suppression and potentially improve cancer treatment strategies.

The initial immune-related therapies were aiming to activate the immune system and were represented by non-specific immunotherapies that didn't aim towards a specific target in the cancer cell (cytokines, interleukins, interferons, etc.). Subsequent efforts tried to identify antigens of the cancer cell and to design monoclonal antibodies (MAB), targeting those antigens. However, it has become clear that these therapies are failing because of the ability of cancers to induce immune tolerance, evasion, and suppression of the immune system, which created a new direction of research - to discover the pathways and the signaling molecules, participating in those immune suppression processes, thus turning them into potential targets

There has been major growth in the understanding of the immune role and its relationship to cancer progression and therapy. The immune system comprises of a multitude of intercon‐ nected cells and tissues, distributed in the body. It basically consists of three general categories of blood cells: 1) lymphocytes (T, B cells and natural killer (NK) cells); 2) myeloid cells (macrophages, dendritic cells, and antigen presenting cells); and 3) granulocytes (neutrophils, basophils, and eosinophils). Simplified, the immune system protects the organism from harmful foreign agents (antigens) by producing specific proteins (antibodies). Those antibod‐ ies circulate until they find and attach to the targeted antigen, thus triggering immune response

The anti-cancer immune response could be largely divided into two types: innate and adaptive immune response. The innate immunity includes the granulocytes, macrophages, dendritic cells, mast cells, and NK cells serving as a first-line protective mechanism, recognizing stressed mutating cells of the organism, and triggering effector mechanism, aiming their eradication. Subsequently, the adaptive immune response is triggered - it consists of specific immune

as anticancer treatments.

78 Immunopathology and Immunomodulation

**2. Basic principles of immune response**

and destruction of the antigen-containing cells.

**2.1. Principles of immune response in solid tumors**

activation of B cells, CD 4- and CD 8-expressing T-lymphocytes.

Normal cells of the organism could become subject of malignant genetic and epigenetic transformation and thus acquire additional characteristics, permitting their uncontrolled proliferation, survival, and dissemination. Such genetic injuries stimulate the innate immune system, which normally serves as a front-line surveillance mechanism, reacting immediately. The NK cells distinguish normal from tumor cells by a complex process of expression of different inhibitory and stimulatory molecules. Specific MHC inhibitory receptors have been described, shedding light over the molecular basis of the activation of the NK cell during the process of natural cytotoxicity of the innate antitumor response. Different receptors frequently referred to as natural cytotoxicity receptors (NCR) are expressed at the surface of the NK cell; they comprise of molecules such as NKp46, NKp30, NKp44, and NKG2D, which bind to their ligands of the MHC class I [2]. NKG2D appears to play either a complementary or a synergistic role with NCRs. The expression of those ligands is induced on the surface of the stressed transformed tumor cells [3,4]. The binding of the MHC-I related ligands to the NKG2D triggers activation of NK cells, NKT and γδ T cells, and CD 8 T cells, which inhibit tumor cytotoxicity and IFN-γ production. Extracellular release of cytoplasmic stress molecules, such as HSP-70, HMGB1, and uric acid, activates macrophages and dendritic cells, resulting in IL-12 production and transition to the adaptive immunity [5].

#### *2.1.2. Adaptive antitumor responses*

The adaptive immune response could be described as the "second-line" response. As a highly specific response to a specific pathogen, it starts relatively later after the initial rapid innate reaction. It is triggered by the dendritic cells, which capture, process, and present tumor antigens to the class I and II MHC, thus stimulating the antigen-specific T- and B-lymphocytes (cellular response) and the specific production of antibodies (humoral component).

Macrophages, dendritic cells, and antigen-presenting cells (APCs) recognize foreign cells and participate in the immune response as they are one of the first responders, approaching a potential harmful antigen. They internalize those extracellular antigens via phagocytosis or receptor-mediated endocytosis; they process and fragment the proteins into peptide sequences that are subsequently presented back at the extracellular membrane surface of the APCs within the context of the Major Histocompatibility Complex (MHC) class II (Figure 1). They also produce large amounts of different cytokines, thus promoting immune response. In cases of inadequately directed immune reaction towards self-antigens, the dendritic cells particularly prevent further autoimmune reaction [6]. In order to prevent self-destruction, the immune system uses endogenous crosstalks—"immune checkpoints"—that normally terminate immune responses after antigens activation of T-cells.

Once the immune response is triggered, the foreign antigen is presented to other cells of the immune complex. More specialized cells, the lymphocytes, encounter the foreign antigen and respond by proliferation and differentiation into different subpopulations. B-lymphocytes arise and differentiate in the bone marrow and enter into the blood stream as functional mature cells. They express a receptor for the antigen on their surface and following encounter with that specific antigen, they start to divide, differentiate into plasma cells, and produce soluble

**Figure 1.** Induction of rapid innate and retarded adaptive immune response (humoral and cellular T- and B-cell re‐ sponse). Tumor cell proteins are degraded into smaller peptides in endosomes/lysosomes in the APCs and are subse‐ quently expressed on the cell surface in MHC class II peptide complexes, which can be recognized by CD4+ T helper lymphocyte cells. T helpers assist B cells to proliferate and mature into antibody-producing plasma cells. Via this route of antigen acquisition, DCs can also present epitopes to CD8+ T cells. This is also known as cross-presentation.

immunoglobulin molecules—antibodies in the circulation. T cells arise in the bone marrow and migrate to the thymus (named thereafter) where they undergo a process of maturation. Immunocompetent T cells leave the thymus and enter into the circulation. There are different T cells classified by their function and phenotype. The largest part of T cells expresses CD 4 glycoprotein and are called T helpers. They enhance the immune process by secreting cyto‐ kines and direct cell-to-cell contact [7]. Other numerous specific functional T-lymphocytes are called cytotoxic (CTLs). They express CD8 glycoprotein and are capable of direct killing of the antigen-containing cells (virally infected or cancerous). Upon encounter of their target, they kill it by induction of apoptosis in the infected or cancerous cell. A part of the lymphocytes remain as sensitized long-living memory cells, recognizing only a single antigen, posed to respond if it is encountered again. The regulatory T cells (T regs) are a small population of T cells and express CD 25 glycoprotein, which participate in the process of self-antigen recog‐ nition, preventing autoimmune reactions [8, 9]. If the immune system functions correctly, its work remains unnoticed, efficiently protecting the individual from a variety of foreign pathogens. In cases of dysfunction, however, severe consequences appear, presented either as immunodeficiency or autoimmunity.
