**1. Introduction**

The idea that the immune system acts as one of the barriers to the emergence and progression of tumors was conceived more than a 100 years ago [1]. Frank Macfarlane Burnet proposed the concept of "antitumor surveillance," which postulated that the immune system acted as a sentinel that controls and eliminates malignant cells [2]. This hypothesis was much debated and the lack of experimental evidence due to the technological limitations of the time generated a heated debate [3]. However, extensive data presented in the literature have since strengthened and expanded this concept [4–8].

Although antitumor immune responses do occur, tumors often develop elaborate strategies of evasion. This fundamental hallmark of cancer encompasses a wide variety of mechanisms and appears to exploit multiple levels and different cell types in the immune system, acting like a network. These mechanisms include (i) immunoediting, where the selection of variants of nonimmunogenic tumor cells (a phenomenon also known as immunoselection) is due to low expression of immunogenic molecules (like TAA) and/or major histocompatibility complex-I (MHC-I) molecules, and (ii) immuno-subversion, where immune suppressor signals

Gene-based Interventions for Cancer Immunotherapy http://dx.doi.org/10.5772/intechopen.80386

These antitumor immune responses rely on innate and adaptive mechanisms. NK (natural killer) cells, part of the innate immune response, recognize MHC-I molecules (through the NKG2D receptor) and eliminate cells that have null or low expression. In addition, danger-associated molecular patterns (DAMPs) and stress-signaling proteins (MICA, MICB, ULBP4) signal an NK attack on cells that have suffered damage and that should be eliminated. Conditions such as irreparable levels of mutations and viral infections naturally trigger this signaling. However, the neoplastic cells can downregulate the expression of these stress markers and MHC-I or may secrete soluble MICA, thus avoiding NK cell

Adaptive immunity also undergoes profound changes during tumor progression. Suppressive immune responses include the formation and recruitment of regulatory T lymphocytes (Treg), which, under normal conditions, inhibit the immune system's response to self-antigens [11]. In the tumor context, this mechanism is subverted to suppress antitumor immune responses, generating tolerance to tumor antigens [13–15]. These infiltrating Tregs contribute to the establishment of a tumor microenvironment abundant in immunosuppressive factors (IL-10, TGF-β, Arg1 and IDO) that influence many different cellular types, including the inhibition of effector T lymphocytes (Teff), generation of myeloid-derived suppressor cells (MDSC) and

impairment of the proper function of dendritic cells (DCs) for presenting antigens [7].

**2. Immune interventions promoting active responses against tumor** 

Therapeutic strategies that target immune activation have shown significantly increased survival and quality of life for cancer patients [17]. Cancer immunotherapy comprises a variety of treatment approaches and combinations, incorporating the specificity of the adaptive immune response (T cells and antibodies) as well as the diverse and potent cytotoxic weaponry of both adaptive and innate immunity [18]. In this section, we provide an overview of

brings interesting perspectives for immunotherapies as discussed below.

The immunosuppressive tumor microenvironment also influences the immune checkpoint status, promoting the expression of inhibitory checkpoint molecules (CTLA-4, PD-1, IDO, LAG3, TIM3 and KIR) to the detriment of stimulatory checkpoint molecules (OX40, CD27, CD28, CD40, CD122 and ICOS) [16]. On the other hand, understanding this phenomenon

are generated, thus disarming antitumor defenses [5, 7, 11].

attack [12].

**cells**

key immunotherapeutic approaches.

The elaboration of appropriate immune responses must include the detection of the "self" and "nonself" antigens. For this, the immune system must not react to self-antigens and, at the same time, must detect threats to the organism, whether internal or exogenous. Tumors are particularly complex since these unwanted cells arise from the body's own tissues. Thus, upon detection of tumor cells, the immune system must strike a fine balance between activation of effector responses and tolerance. The immune system exploits the tenuous differences between normal cells in homeostasis and intrinsically related tumor cells.

Considering the high rate of mutation in tumors, the newly formed protein variants generate neoepitopes that may serve as targets for the detection and elimination of these aberrant and decontextualized cells by the immune system. These neoantigens can be, for example, the result of mutations caused by dysfunctional chromosomal recombination, such as the Philadelphia chromosome, generating a BCR-ABL gene fusion that did not previously exist in the body. This is a classic example of tumor-specific antigen (TSA), as seen in **Table 1**. Among the solid tumors, melanoma has the highest mutation rate (0.5 to >100 mutations per megabase), which reinforces the hypothesis that it is a highly immunogenic tumor [9]. Another characteristic of tumor cells is that they can express, or overexpress, genes outside the homeostatic context of their microenvironment, such tumor-associated antigens (TAAs) include oncofetal genes (linked to embryogenesis) or tissue markers, such as in melanoma (MAGE) or in breast cancer (HER2) [10]. These neoantigens and deregulated/overexpressed proteins are important targets for immunotherapeutic approaches.


**Table 1.** Examples of TAA and TSA recognized by T cells.

Although antitumor immune responses do occur, tumors often develop elaborate strategies of evasion. This fundamental hallmark of cancer encompasses a wide variety of mechanisms and appears to exploit multiple levels and different cell types in the immune system, acting like a network. These mechanisms include (i) immunoediting, where the selection of variants of nonimmunogenic tumor cells (a phenomenon also known as immunoselection) is due to low expression of immunogenic molecules (like TAA) and/or major histocompatibility complex-I (MHC-I) molecules, and (ii) immuno-subversion, where immune suppressor signals are generated, thus disarming antitumor defenses [5, 7, 11].

**1. Introduction**

strengthened and expanded this concept [4–8].

90 In Vivo and Ex Vivo Gene Therapy for Inherited and Non-Inherited Disorders

The idea that the immune system acts as one of the barriers to the emergence and progression of tumors was conceived more than a 100 years ago [1]. Frank Macfarlane Burnet proposed the concept of "antitumor surveillance," which postulated that the immune system acted as a sentinel that controls and eliminates malignant cells [2]. This hypothesis was much debated and the lack of experimental evidence due to the technological limitations of the time generated a heated debate [3]. However, extensive data presented in the literature have since

The elaboration of appropriate immune responses must include the detection of the "self" and "nonself" antigens. For this, the immune system must not react to self-antigens and, at the same time, must detect threats to the organism, whether internal or exogenous. Tumors are particularly complex since these unwanted cells arise from the body's own tissues. Thus, upon detection of tumor cells, the immune system must strike a fine balance between activation of effector responses and tolerance. The immune system exploits the tenuous differences

Considering the high rate of mutation in tumors, the newly formed protein variants generate neoepitopes that may serve as targets for the detection and elimination of these aberrant and decontextualized cells by the immune system. These neoantigens can be, for example, the result of mutations caused by dysfunctional chromosomal recombination, such as the Philadelphia chromosome, generating a BCR-ABL gene fusion that did not previously exist in the body. This is a classic example of tumor-specific antigen (TSA), as seen in **Table 1**. Among the solid tumors, melanoma has the highest mutation rate (0.5 to >100 mutations per megabase), which reinforces the hypothesis that it is a highly immunogenic tumor [9]. Another characteristic of tumor cells is that they can express, or overexpress, genes outside the homeostatic context of their microenvironment, such tumor-associated antigens (TAAs) include oncofetal genes (linked to embryogenesis) or tissue markers, such as in melanoma (MAGE) or in breast cancer (HER2) [10]. These neoantigens and deregulated/overexpressed

between normal cells in homeostasis and intrinsically related tumor cells.

proteins are important targets for immunotherapeutic approaches.

**Human tumor Antigenic protein**

Prostate carcinoma Prostate-specific antigen (PSA)

Colon carcinoma Carcinoembryonic antigen (CEA)

Melanoma, esophageal and liver carcinoma MAGE Melanoma Tyrosinase Breast and ovarian carcinomas HER2/Neu

Head-and-neck carcinoma Caspase 8 Chronic myelogenous leukemia (CML) BCR-ABL

**Table 1.** Examples of TAA and TSA recognized by T cells.

These antitumor immune responses rely on innate and adaptive mechanisms. NK (natural killer) cells, part of the innate immune response, recognize MHC-I molecules (through the NKG2D receptor) and eliminate cells that have null or low expression. In addition, danger-associated molecular patterns (DAMPs) and stress-signaling proteins (MICA, MICB, ULBP4) signal an NK attack on cells that have suffered damage and that should be eliminated. Conditions such as irreparable levels of mutations and viral infections naturally trigger this signaling. However, the neoplastic cells can downregulate the expression of these stress markers and MHC-I or may secrete soluble MICA, thus avoiding NK cell attack [12].

Adaptive immunity also undergoes profound changes during tumor progression. Suppressive immune responses include the formation and recruitment of regulatory T lymphocytes (Treg), which, under normal conditions, inhibit the immune system's response to self-antigens [11]. In the tumor context, this mechanism is subverted to suppress antitumor immune responses, generating tolerance to tumor antigens [13–15]. These infiltrating Tregs contribute to the establishment of a tumor microenvironment abundant in immunosuppressive factors (IL-10, TGF-β, Arg1 and IDO) that influence many different cellular types, including the inhibition of effector T lymphocytes (Teff), generation of myeloid-derived suppressor cells (MDSC) and impairment of the proper function of dendritic cells (DCs) for presenting antigens [7].

The immunosuppressive tumor microenvironment also influences the immune checkpoint status, promoting the expression of inhibitory checkpoint molecules (CTLA-4, PD-1, IDO, LAG3, TIM3 and KIR) to the detriment of stimulatory checkpoint molecules (OX40, CD27, CD28, CD40, CD122 and ICOS) [16]. On the other hand, understanding this phenomenon brings interesting perspectives for immunotherapies as discussed below.
