**3. The influence of the host's immune responses on colon cancer growth**

### **3.1 Cellular immune rejoinders**

The immune system reactions, as innate and adaptive, have different impacts on CC growth and management. The inflammation process is described as one of the innate responses. The inflammation process is initiated and exacerbated by various types of immune cells including macrophages, neutrophils, and mast cells, for their activation, margination, extravasation, and migration to the damaged tissue [24]. The preferred role of inflammation against cancer is at stages I and II. Moreover, the inflammation role was to activate the adaptive immune cells by activating the innate system's antigen-presenting cells, such as dendritic cells. Additionally, natural killer

#### **Figure 4.**

*The proapoptotic BAX protein and antiapoptotic BCL-2 protein signaling effects [21].*

(NK) cells and macrophages of the innate system help capturing the cancer cells and releasing immunostimulatory cytokines to activate the adaptive system [25].

On the other hand, cancer is addicted to proliferative and survival signals in the cancer microenvironment as inflammation. Soluble factors, cytokines, and chemokines influence inflammation. They are secreted by cancerous cells with the innate cells recruited to the microenvironment, such as macrophages and mast cells. The depletion of mast cells or macrophages prevented the APC from mutating and preventing intestinal polyps' initiation. This confirms the role of immune cells and their soluble factors in intestinal cancer initiation and progression [22, 24, 26].

Moreover, T-lymphocytes, T-helper (TH or CD4), NK cells, and dendritic cells are associated with CC survival enhancement regarding the adaptive immune system's role in controlling CC. Additionally, cytotoxic T-lymphocytes (CTL or CD8) and TH cells enhance the cancer cells' apoptosis, engulfment, detection, and antibody production against cancer cells. Furthermore, B-cells' antibodies that target specific surface antigens are limited by the presence of the tumor-specific antigens, such as the carcinoembryonic antigen, to capture it by the antibodies and enhance the cancer cells removal [27].

In terms of CC immunotherapies, numerous FDA-approved vaccinations defend against viruses known to cause certain forms of cancer. Vaccination against human papillomavirus (HPV), for example, can protect against six forms of cancer, while a vaccine against hepatitis B virus (HBV) helps protect against some types of liver cancer. Unfortunately, however, there is no colorectal cancer vaccination available [28].

On the other hand, chimeric antigen receptor-T (CAR-T) cell immunotherapy is a unique technique that is genetically designed to recruit T-cells against malignant

*DOI: http://dx.doi.org/10.5772/intechopen.105982 Colorectal Cancer Stages, Progress, Genetic Predisposition, and Immune Surveillance*

illness. CAR-T cell therapy has led to success in hematological malignancies, and it has long been advocated for solid tumors such as colorectal cancer (CC). However, this strategy did not meet expectations given solid tumors' intrinsic obstacles provided to CAR-T cells, owing to a lack of tumor-restricted antigens and undesirable adverse effects. New techniques, such as designing T-cells with immune-activating molecules, localized delivery of T-cell, bispecific T-cell engager, and combinatorial target-antigen recognition, are proposed to overcome many hurdles to ameliorate the challenging conditions of CAR-T cells in CC [29].

Furthermore, CAR-natural killer (NK) cells have received widespread interest due to their safety in clinical applications, the method for identifying cancer cells, and the quantity of clinical specimens. CAR-NK cells have been shown in preclinical and clinical trials to be capable of combating hematological malignancies as well as solid tumors such as CC. However, the use of CAR-NK cell therapy in solid tumors presents unique challenges, such as the expansion and activation of primary NK cells in vitro, the selection of CAR targets, the survival time of CAR-NK cells in vivo, NK cell storage and transportation, and the efficiency of NK cell transduction [30].

### **3.2 Cytokines and chemokines**

Cytokines are classified into proinflammatory, immunostimulatory, and immunoinhibitory cytokines. For proinflammatory cytokines, the, interleukin (IL)-8 (chemokine), IL-1, IL-6, tumor necrosis factor (TNF)-α, and vascular endothelial growth factor (VEGF) serum levels are associated with cancer development and considered as predictive tools. Moreover, macrophages release IL-1, which contributes to fever and T-cell and macrophage activations. Furthermore, IL-6 is released by macrophages, endothelial cells, and T-cells. IL-6 inhibits the production of acute-phase proteins in the liver and promotes the proliferation of antibody-producing cells. On the other hand, IL-8 is a chemoattractant generated by macrophages that attracts immune system cells and phagocytes to the site of inflammation. Finally, TNF-α is mainly secreted from macrophages and TH cells, which has a cytotoxic reaction against cancer cells and enhances the activity of phagocytic cells. As a result, TNF-α and IL-1β are emerging as potential targets for drug candidates in anticancer therapy [24]. Furthermore, TNF-α antagonists are well studied in the rheumatoid arthritis, and IL-1β antagonists are used for inflammatory disorders characterized by excessive IL-1β production [27]. On the other hand, VEGF is secreted by the cancer cells to improve cancer cell vasculature (angiogenesis) [12].

For immune system stimulation, IL-2, IL-4, IL-5, IL-12, IL-18, and interferon (IFN)-ϒ are immune-stimulatory cytokines. The immune-stimulatory cytokines activate the growth, differentiation, and maturation of CTL, TH cells, NK cells, and dendritic cells. Additionally, macrophages, lymphocytes, and NK cells produce IFN-ϒ, in which IFN-ϒ is significant macrophage and NK cells activator. As a result, IFN-ϒ enhances major histocompatibility class I expression to activate CTLs. Moreover, IL-2 is secreted by TH cells and co-stimulates the proliferation of TH cells, CTLs, and B-cells, which activates NK cells. Additionally, IL-18 is primarily secreted by macrophages and promotes NK cells cytotoxicity as well as T-cell's IFN-ϒ production. Furthermore, dendritic cells and macrophages release IL-12, which contributed to the TH-1 cell differentiation, NK cell, and T-cell activations. On the other hand, the lymphocytes and macrophages produce IL-4, which is involved in B-cell activation,

differentiation of TH-2 cells, and TH-1 cells suppression. Finally, IL-5 is released by TH cells and mast cells and has the primary activity of activating and chemoattracting eosinophils [22, 31].

The immune regulatory system is activated by the secretion of IL-10 and TGF-β from the cancerous cells, tumor-associated macrophages, or immune cells, such as TH-2 cells. In addition, it enhances the activation and expression of the immune checkpoint molecules, such as cytotoxic T-lymphocyte antigen-4 and programmed cell death protein-1, which can inhibit the immune stimulatory signals activation between antigen-presenting cells and the CTLs to capture the cancer cells [31]. Moreover, IL-10 is involved in suppressing macrophage phagocytosis and B-cells' activation [11, 12, 27]. To summarize the role of cytokines and chemokines in the CC angiogenesis or immune system recognition, **Figure 5** illustrates the recently found relation between the CC and the cytokines [32].
