**3. Principles of cancer immunobiology: Immunoediting, surveillance, and immune escape**

The importance of intact immune surveillance in controlling the outgrowth of neoplastic transformation has been known for decades [10]. With the discovery of the cellular oncogenes, it became evident that human cancers arise from normal cells and harbor various genetic and epigenetic alterations, generating potentially recognizable by the immune system cancer neoantigens [11]. Being of host origin, cancer cells share features of the host. The plastic nature of tumors makes them adaptive in rebounding from clinical regimens of radiotherapy/ chemotherapy that are traditionally used. The tumor progression can be described as a continuum of multiple clonal expansions, each of which triggered by the fortunate acquisition of an enabling mutant genotype. Even when the vast majority of cancer cells are killed by a cytotoxic chemotherapy drug, a small number of residual cells are primarily or become secondarily resistant to that agent. They can be sufficient enough to seed the subsequent tumor regrowth that is resistant to the previously used chemotherapy agent. This leads to the concept of selection of tumor cells and evolving resistance that becomes a key disease progression feature; development and progression of cancer is driven by the selection of cells that survive conditions that are normally lethal. Resistance to any normally lethal condition (radiotherapy, chemotherapy, etc.) can be selected by the cancer cell population evolution because of the genetic plasticity, which is an important feature of the cancer cell [12].

The tumor development is a multi-step process, requiring the acquisition of several biological features: 1) sustained proliferation signaling; 2) evasion of growth suppression; 3) apoptosis escape; 4) uncontrolled growth and reproduction; 5) angiogenesis induction; and 6) invasion and metastasizing potential. These hallmarks of the tumor cells ensure their survival, prolif‐ eration, and dissemination [13]. There are other characteristics that facilitate the acquisition of these hallmarks by the cancer cells, such as the tumor-associated stromal microenvironment and inflammation, genomic instability, and mutations, mediating the process of tumorigenesis [14]. There are two more features that are functionally important for the development of cancer hallmarks. The first feature involves major reprogramming and deregulation of cellular energy metabolism in order to continuously ensure cell growth and proliferation. The second feature involves active tumor escape of the immune system destruction and elimination. This capability highlights the dichotomous role of the immune system that both suppresses and enhances cancer initiation, promotion, and progression [15-17]. Both of these features may well prove to facilitate the initiation and progression of many forms of malignant human solid tumors [14].

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‐

**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.

80 Immunopathology and Immunomodulation

There is a theory suggesting that cells and tissues are constantly monitored by an ever-alert immune system, and that such immune surveillance is responsible for recognizing and eliminating the vast majority of incipient cancer cells and thus nascent tumors. According to this logic, solid tumors that do appear have somehow managed to avoid detection by the immune system or have been able to limit the extent of immunological killing, thereby escaping eradication. This is a process called immunoediting—a tumor mechanism, exerting an extrinsic suppression; it occurs only after a malignant cancerous transformation has already occurred and the intrinsic tumor suppressor mechanisms have already failed. The cancer immunoedit‐ ing roughly consists of three sequential phases: elimination, equilibrium, and escape. In the first phase, the body immune system successfully detects cancer cells and eliminates them efficiently [18,19]. In the equilibrium phase the immune system obstructs tumor growth, but is unable to completely eradicate the tumor. This step is thought to be continuous in time and it could either progress to the last escape phase or reverse backwards, leading to complete tumor eradication by the immune system. If this second phase continues for a longer period of time, the immune system is incapable of tumor eradication and continuously interacts with the tumor, thus sculpturing or editing the tumor genetics [20-22]. In the last phase, the tumor growth is no longer controlled and blocked by the immune system and the tumor spreads and produces clinically apparent diseases [23].
