**2. Immunoediting and immunosurveillance**

vants and adjuvant treatments with conventional anticancer strategies, such as surgical debulking, radiation therapy, and chemotherapy. In conventional anticancer treatment, the chemotherapeutic-induced immunosuppression inhibits the anticancer efficiency of cell therapies, which are based on activated lymphocytes for eradication of tumor cells, enhancing susceptibility to infections. The majority of conventional chemotherapeutic agents interfere with hematopoiesis and subsequently with the immune system, affect‐ ing the surveillance of cancer cells leading to the promotion of tumor development and growth. Furthermore, cancer surgery causes tremendous alterations in the neuroendo‐ crine, metabolic, and immune systems constituting the stress response, which may lead to infection and cancer recurrence. Generally by using an integrative medicine immu‐ notherapeutic approach, where alternative medicine practice which follows a multitar‐ geted and bidirectional regulation may compensate for deficiencies of conventional orthodox western medicine, which is characterized by specificity, we may achieve a synergistic effect concerning circumvention of tumor-induced immunosuppression and enhancement of antitumor immunomodulation followed by minimization or elim‐ ination of side effects, prolonging the survival rate of advanced stage and metastatic cancer patients promoting their quality of life. The key is to treat each cancer patient under a personalized evidence-based medicine approach, which must rely on clinom‐ ics, including transcriptomics, genomics, immunomics, lipidomics, glycomics, proteo‐ mics, metabolomics, nutrigenomics, and mainly epigenomics whose alterations in their noncoding RNA genes are reversible especially with immunonutrition. The precise im‐ munotherapeutic approach against cancer may act synergistically with conventional anticancer therapies, such as surgery, chemotherapy, and radiotherapy combined with therapies based on molecular targeting, which are tailored for each patient on a phar‐ macogenomic basis, and they can be combined with nanomedicine for specific molecu‐ lar targeting and circumvention of biological milieu interactions, which may enhance tremendously therapeutic efficacy with simultaneous reduction of systemic toxicity.

**Keywords:** Immunosurveillance, immunoediting, tumor-induced immunosuppression, immunoresistance, immunomodulation, immunotherapy, immunonutrition, personal‐

The strategies to fight cancer are composed of mechanisms including surgery since 1600 BC, physics including radiotherapy since 1896, chemistry including chemotherapy since 1942, and biology including immunotherapy since 1976. Although immunotherapy has a long history that has been evaluated for more than a century, only recently has it entered a renaissance phase with anticancer biological agents, including the first monoclonal antibody approved in 1997, interleukin-2 (IL-2) cytokine approved in 1998, the first cellular immunotherapy as therapeutic vaccine approved in 2010, and the first checkpoint inhibitor approved in 2011, which has been succeeded by many more approved immunotherapeutic agents [1]. The cancer immunosurveillance hypothesis proposed by Ehrlich in 1909, modified by Burnet and Thomas in 1957, refers to the immunological resistance of the host against cancer development.

ized or precision cancer medicine, evidence-based medicine, omics

**1. Introduction**

18 Immunopathology and Immunomodulation

The current term is cancer immunoediting, which is composed of three phases: elimination, equilibrium, and escape. Tumor cells, which successfully navigate these phases, are capable of evading destruction by the immunity system of the host [2]. Generally, the main component of the defensive army of the host's immune system for fighting tumors is composed of cytotoxic T cells (CTLs).

The elimination phase is a process, where the immune system components recognize trans‐ formed cells, eliminating them with the use of the innate and adaptive immune system [3]. Elimination consists of four phases, where the first phase of elimination initiates the antitumor immune response, after the cells of the innate immune system have detected a growing tumor mass, which has caused damage to the local tissue after it has been through stromal remodel‐ ing. This induces inflammatory signals, which recruit into the tumor-site cells of the innate immune system, such as macrophages, dendritic cells, and infiltrating lymphocytes such as natural killer cells and natural killer T cells that release interferon-gamma (IFN-γ). Τhe second phase of elimination involving IFN-γ induces immunogenic tumor cell death (ITCD), and it activates the release of chemokines, such as CXCL9, CXCL10, and CXCL11, which inhibit angiogenesis inducing immunogenic necrotic tumor cell death, whose apoptotic bodies are phagocytosed by dendritic cells in the draining lymph nodes, as a bystander killing effect (BKE). The subsequent inflammation releases cytokines and chemokines, which attract additional immune cells. During the third phase of elimination, the reciprocal release of cytokines IL-12 and IFN-gamma transactivates macrophages and natural killer cells, expand‐ ing tumor cell death by apoptosis or PCD type I and releasing reactive oxygen and nitrogen intermediates. Tumor-specific dendritic cells in the draining lymph nodes activate the differentiation of Th1 cells, which mediate the production of killer T cells or CD8+ T cells. In the fourth phase of elimination, tumor-specific cytolytic T lymphocytes CD8+ and CD4+ T cells infiltrate the tumor site after recognition of tumor-specific or tumor-associated antigens, such as MHC class J and class II molecules, which in synergy with B cells that produce antibodies, such as IgG, IgA, IgM, IgD, and IgE, facilitate innate and adaptive immune mechanisms, which mediate release cytokines leading to immunogenic tumor cell death. The cancer cells that are not eradicated by the elimination phases of the immune system proceed to the equilibrium phase, where IFN-gamma and lymphocytes prevent expansion of tumor cells that are geneti‐ cally unstable and mutate rapidly. All the tumor cell variants, which have evaded immune pressure due to acquired resistance to the elimination phases where the balance between the immune response and the tumor cells is driven toward tumor growth that expands in an uncontrolled manner with nonimmunogenic transformed cells, may lead to malignancies by entering the escape phase directly [4–9].

Furthermore, there are different types of nonimmune surveillance against tumors, including genetic surveillance, which is based on DNA repair and checkpoint control, intracellular surveillance related to apoptosis or type I PCD, intercellular surveillance linked to the tumor microenvironment, and epigenetic surveillance related to the structure of chromatin and specifically the stringency of imprinting [10–13].

Circumventing immune destruction is one of the hallmarks of cancer pathogenesis in addition to evading growth suppressors, deregulating cellular energetics, enabling replicative immor‐ tality, inducing angiogenesis, activating invasion and metastasis, sustaining proliferative signaling, and resisting cell death, which may lead to the uncontrollable promotion of tumor burden at the expense of the immune system [14].
