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Immunobiology behind Colorectal Cancer

Colorectal cancer (CRC) affects a relatively large portion of the population in the United States. Approximately 160,000 people in the U.S. are diagnosed with CRC every year, and about 57,000 patients die from the disease. It is the second leading cause of death among adults, and metastasizes to the lymph nodes, liver, and lungs which are the main cause of death in patients with the disease. Numerous studies on the immunobiology of CRC have shown that the human body exhibits various immune responses against CRC to ensure survival. However, a majority of these immune responses are almost always ineffective against tumor growth and progression due to the suppression/inhibition of critical immunobiological factors. In recent years, new immunological developments have emerged in CRC research particularly immunotherapy. In this review article, we will discuss the role of immunobiological factors that could serve as potential prognostic markers in CRC detection. Immune cells; effectors T cells (CD4 and CD8), natural killer (NK) cells, dendritic cells (DC), and regulatory T (Treg) cells that play an active role in CRC development will be discussed. Additionally, the possibilities by which these cells can be suppressed as plausible immunotherapeutic regimens of the disease will also be covered.
Keywords: CRC, Immunobiological markers, Immune cells, immunotherapy.
Cancer is the second leading cause of death behind heart disease in the United States and is the third most common cancer worldwide [1, 2]. CRC is predominant within Western countries, which account for over 63% of all cases [3]. In the United States, males have a slightly higher rate of CRC as compared to the female. Survival rates for people with CRC vary based on the stage of the disease when diagnosed. About 90% of CRC cases affect people over the age of 50 years, thus colonoscopies are recommended at or over the age of 50 years [3]. Other methods of diagnosis include detection of biomarkers such as carcinoembryonic antigens (CEA) [3-6]. To date, the major treatment regimen for CRC is surgery followed by chemotherapy or radiation therapy. To circumvent the limited treatment options and to increase survival against CRCs, alternate forms of treatment are being extensively explored. Immunotherapy is a new treatment that is being extensively researched with a potential to treat CRCs.
Several studies have looked into equipping immune cells such as effector T cells (CD4 and CD8 cells), macrophages (Mɸ), dendritic cells (DC), and natural killer (NK) cells in their natural roles against CRC [7]. One such immune cell, the anti-tumor lymphocyte, has been discovered as an even stronger prognostic factor for CRC than tumor-node-metastasis (TNM) classification [7]. However, CRC cells have the ability to pervade the effects of these lymphocytes, preventing CRC recognition [7, 8]. T cells are also known to have anti-tumor properties. In particular, T cell receptors link with peptide, which are degraded antigens of tumors, and exhibit an antigen-specific anti-tumor immune response. Another immune cell, the natural killer cell (NK cell), can target certain cancer cells depending on the cancer cell type and based on the signals that the cells give off, such as stress signals or signals resulting from DNA damage; subsequently, the NK cell can dispose of the tumor cell in a variety of ways [9-11].
There has been significant research concerning the global reach of CRC [1, 2]. CRCs development occur in individuals who are genetically predisposed and in conjunction with certain environmental stimuli [1]. In this review article, research that has and is currently being undertaken concerning the role of immunobiological factors and its role in immunotherapy of colon cancer is highlighted. Immunotherapy based on immunobiological factors (cytotoxic CD8+ T lymphocyte, Treg, NK cells, DC cells, and Mɸ etc.) can function as an alternate source of treatment along with chemotherapy and radiation therapy. However, immunotherapy may help patients with advanced CRC. Some immunotherapeutic approaches discussed will include peptide vaccines, dendritic cell-based cancer vaccines, antibody-based cancer immunotherapy, DNA vaccines, viral vector-based vaccines, adoptive cell transfer therapy, autologous vaccines, and allogeneic vaccines. These immunotherapeutic approaches incorporate the use of tumor associated antigen (TAA)-derived peptides, whole tumor cells, in vitro-generated DCs, and/or viral vector-based cancer vaccines. By equipping the body’s own forces, immunotherapy provides an interesting and practical new option for CRC patients [1, 10, 11]. Along with NK cells and effectors T-cells, DCs, which are antigen-presenting cells (APCs) that are commonly used in cancer vaccines in part due to their immune response inducing properties, and T-regulatory cells [1, 10, 11] will be covered in this review
CRC growth and development
CRC is closely tied to the suppression of adenomatous polyposis coli (APC), a tumor suppressor gene that inhibits the production of the cancer-causing β-catenin protein [12-14]. This suppression is brought about usually by chromosomal instability, where several portions of chromosomes are deleted and cause degradation of APC and other tumor suppressor genes such as p53 and Smad 4 (S-Mothers Against Decapentaplegic Proteins) family member 4 [12-16]. APC plays a key role in the regulation of Wnt signaling pathway. The Wnt signaling pathway controls various cellular functions, including proliferation, differentiation and the production of β-catenin [17]. Additionally, Wnt signaling pathway involves in the interaction of Wnt factors and the frizzled cell receptors. The binding of Wnt ligand to its receptor protein named Dishevelled (dsh) prevents the phosphorylation of β-catenin. Phosphorylated β-catenin allows the latter to accumulate in the cell’s cytoplasm and nucleus, causing a chain reaction that promotes gene transcription, conducive to mitosis which eventually leads to a greater production of the CRC cells [17]. Therefore, the tumor-suppressor gene APC can play multiple inhibitory roles in CRC tumor enviroment [18] by the phosphorylation of β-catenin [12, 17, 18]. The APC forms a destruction complex alongside Axin and GSK-3β (glycogen synthase kinase-3) that stymies β-catenin while Wnt signaling is turned off [19, 20]. Also, APC causes the translocation of β-catenin out of the nucleus and binds to it to prevent activation of the tumor cell factor (TCF), which may induce Wnt signaling pathway [18]. Several missense mutations may lead to the destruction of APC gene [20]. The lack of APC may lead to familial adenomatous polyposis (FAP), a disorder characterized by the increasing number of adenomatous polyps lining the walls of the colon [12]. FAP contributes an increased risk of inherited colon cancer. Mutations in β-catenin itself may also lead to the prevention of its own degradation and lead to CRC development [17].
In a majority of cases, microsatellite instability (MSI) contribute to the development of CRC, where the DNA mismatch repair system that repairs DNA replication errors is severely impaired [1, 11, 12, 16]. Therefore, MSI is a potential marker for colorectal cancer [14]. MSI associated genes, the mutL homolog 1 and 2 (MLH1 and MSH2) are frequently mutated or epigenetically silenced (may need a reference for this here)and are investigated in CRC developemnt [12, 14, 16, 21]. Hereditary nonpolyposis coli (HNPCC) or Lynch syndrome are known to arise from mutations in these genes [12, 16].
Heredity plays a key role in CRC development, but does not account for all cases [12, 16]. The majority of CRC cases are tied to alterations in the tumor microenvironment, not necessarily inherited genetic changes [21]. About 70-75% of cases of CRC occur sporadically [22]. Countries that have a high population of CRC patients include the United States, Canada, and other European nations, while nations with lower populations of CRC patients include countries from Asia and Africa, suggesting that Westernized nations may have a predisposition towards CRC based on their lifestyles and diet [1, 3]. Western diets, characterized by large quantities of red meat and processed foods [1], and obesity, which is relatively widespread in the United States, are thought to affect CRC; hyperinsulinemia, which can be caused by obesity, has been shown to promote cell proliferation and inhibit apoptosis due to the increase in (define) IGF-1 expression [1, 23][1, 17]. Another factor that has been studied in conjunction with CRC includes inflammatory bowel disease, which has been found to increase the risk of incidence of the disease [3, 22].  Meta-analysis of CRC risk factors has led to the conclusion that the above factors, as well as smoking correlate with a significant increase in CRC development [23]. However, the effects of alcohol, in CRC remains unknown with contradictory results [1, 23].
CRC and Immunotherapy
Perhaps one of the most interesting developments in the immunological spectrum of CRC research is the emergence of immunotherapy. Immunotherapy promotes cancer inhibition by launching an immune response or attack against tumor cells in response to specific antigens [11, 24-26]. However, the lack of tumor-specific antigens can potentially trigger bodily harm in the process of purging, therefore, limiting the immune response of immunotherapy [11, 24-26]. The carcinoembryonic antigen (CEA) is the most widely studied antigen in CRC immunotherapy. Promoting the aggregation of cancer cells has led CEA to be used even as a diagnostic marker for CRC disease progression [11, 24-26]. The plasma-membrane associated glycoprotein is overexpressed not only in cancers of the digestive system but also in breast cancers [11]. In liver cancer, the loss of the expression of one type of CEA (CD66a) led to significantly larger tumors [27]. Interferon β (IFN-β) and Interleukin 2 (IL-2), two important cytokines are known to play various immune-based roles, have been studied in conjunction as a potential gene therapeutic method of inducing immune responses from CEA [28]. CEA is also present in normal cells, though, which prevents a strong immune response from being elicited by immunotherapeutic methods due to tolerance buildup? [11, 24-26]. Other antigens studied for a targeted immune therapeutic approach include MUC1 (mucinous glycoprotein-1). Mucin, a transmembrane glycoprotein which is present on the surface of epithelial cells, Guanylyl cyclase C (GCC), another glycoprotein that acts as a receptor for guanylyl and uroguanylin, Wilms’s tumor gene 1 (WT1) and melanoma-associated antigen gene (MAGE) [11, 29-31].
Cancer vaccines are active therapeutic approaches designed to prompt the immune system to signal to tumor antigens and cause immune reactions. Cancer vaccine development is hindered by the inability to find tumor specific antigens??. Several types of cancer vaccines have been proposed, one of which is the autologous tumor cell vaccine. The autologous tumor cell vaccine is produced by the removal of tumor cells from patients, converting the cells into vaccines and giving the vaccine back to the patient [11]. Autologous tumor cell vaccines could potentially attack all tumor antigens, but since tumor cells have few tumor-specific antigens, the response is generally weak. The removal of tumor cells from areas filled with bacteria such as the colon has been a cause of concern for some, slowing down the widespread distribution of autologous tumor cell vaccines; although in some studies there is currently no proof as to whether or not bacteria transported from the colon actually affect patients [32, 33]. The heterogenic cell makeup of a tumor means that autologous tumor cell-based treatments may not be able to offer an encompassing response to every type of tumor cell present [34]. With autologous tumor cell vaccines lies the risk of potentially aiding the proliferation of more CRC cells; the treatment of cell vaccines with UV radiation has been shown to reduce tumor proliferation [35].
Similar to the autologous tumor cell vaccine is the allogeneic tumor cell vaccine. Instead of using cells sourced straight from patients, allogeneic tumor cell vaccines employ the use of cells from different sources of the same species [34]. These cells lines can be grown in labs to produce specific TAAs (Tumor Associated Antigens) (define earlier and remove here) [34]. Allogeneic tumor cell vaccines also may not contain patient-specific tumor antigens.
CRC and Immunobiology of TCells
T-cells and their role in cancer and CRC
Tumor cells play an active role in cell-mediated immune response [36-38]. They degrade TAAs into peptides, which are then presented in the context of major histocompatibility complex (MHC) class I molecules [10]. A critical part of the anti-tumor immune response includes the interaction of T cell receptors (TCRs) with peptides and MHC class I molecules [36-38]. Research has shown that one of the most effective T-cell subsets that initiate an effective anti-tumor response includes CD8+ Tcells. CD8+ Tcells recognize TAA-derived peptides that have been bound to tumor cells by MHC class I molecules. In order to activate CD8+cytotoxic T lymphocytes (CTLs), in the presence of MHC class I molecules, antigen presenting cells (APCs) must have TAA-derived peptides present on their surface. The CD4+ T cells identify peptides that correspond with MHC class II molecules on APCs and aid in enhancing the persistence of antigen-specific CD8+ CTLs, which is carried out through the excretion of interleukin (IL)-2 and interferon (IFN)-γ. Therefore, T-cells play a critical role in immunotherapy. By evaluating their capabilities, T-cells can be exploited to be used in new treatments that combat cancer, especially CRC [10].
A type of immunotherapeutic treatment that is currently being researched is adoptive T cell therapy (ACT).  In ACT, T cells have specific immune responses which can increase the efficiency of immune system to fight against cancer [39-41]. ACT can activate the regression of specific human diseases through the infusion of tumor-specific T cells. By utilizing the T cell’s ability to identify and eliminate target cells, ACT aids in late-stage cancer treatment [42]. Genetically engineered T lymphocytes express a murine TCR against human CEAs, tumor-associated proteins that are typically overexpressed in colorectal adenocarcinoma have been developed to target metastatic CRC [43, 44]. In one study autologous T lymphocytes genetically modified were adoptively transferred into the patients using interleukin-2 [39-41]. In the adoptively transferred cells, the efficiency of transduction ranged from 79 to 90%. After the ACT, protein level was dropped by 74-99% in all three patients [43, 44]. Patient 1 experienced a 17% reduction in metastatic cancer to the lung two months after the ACT, patient 2 had no response and patient 3 experienced a 34% reduction in metastatic cancer to the liver, lung and lymph nodes three months after ACT [43, 44]. However, after the ACT, all three patients developed inflammatory colitis. The CEA-reactive T cells transferred to the patients caused the destruction of the colonic mucosa, presumably because of the lymphocyte recognition of normal CEA levels in the colonic mucosa [43, 44].
Additionally, T cells can be utilized with chimeric antigen receptors (CARs). CARs are receptors that are linked to T cell activation domains using zeta chain of the intracellular domain of cluster of differentiation 3? CD3??(define) that recognize specific region on antibodies. They can trigger T cell activation, but research shows that there has been limited in vivo expansion [43-45]. Although the success and number of studies using CARs are limited; some investigations have shown their potential in cancer treatment. A study by the University of Pennsylvania created a lentiviral vector to express CARs with specificity for B cell antigen Cluster of differentiation 19 (CD19), with the combined effect of CD137 and CD3-zeta signaling domains. CAR-modified T cells were infused into patients with chronic lymphocytic leukemia, causing a delay in the development of tumor lysis syndrome and lymphopenia [45]. Patients also experienced a loss of B cells and leukemia cells that expressed CD19, possibly due to the CART19 cell-mediated elimination of benign B cells. If the expression is limited to both benign and malignant B cells, the CAR T cells would cause a long-term B cell deficiency [45]. Another study found genetically engineered T cells expressed CARs at high levels/concentrations for six months. Each CAR-expressing T cell killed approximately 1000 chronic lymphocytic leukemia cells [43-45].
By applying the current knowledge about T cell immunotherapy, it is possible to find new and more effective immunotherapeutic treatments targeted for CRCs.
T regulatory cells
Within the umbrella of T cells lies the subpopulation of T-regulatory cells (Tregs). A subset of CD4+ T-cells, they play a major part in managing immunological responses, including controlling unresponsiveness??? to self-antigens and suppressing excessive immune responses that are damaging to the host [7]. The primary function of regulatory T cells is to prevent autoimmune diseases by maintaining self-tolerance. Immunological self-tolerance is crucial for preventing autoimmune diseases and maintaining immune homeostasis [46-48].
Research has shown that regulatory T cells, also known as suppressor cells, have quite an impact on the immune system. Tregs have been known to be beneficial and detrimental; while they can assist in limiting chronic inflammatory diseases like asthma, they can equally limit the body’s anti-tumor response [46-48]. The risk of developing cancer was shown to be greatly higher when inflammatory responses to pathogenic bacteria were poorly regulated [46-48]. Treg cells are thought to act under the transcription factor forkhead box P3 (FoxP3), which controls several facets of the cell, including preserving functionality [39]. They are also identified by the presence of CD4+ and CD25+ surface markers [7]. It has been uncertain as to whether or not the cytokines IL10 and TGF-β (Transforming growth factor-β) are completely beneficial to the operations of Tregs, they are known to assist in overall Treg function, but there is conflicting evidence between in vitro and in vivo studies as to whether or not the two are required for Tregs to perform at peak level [46-48].
Tregs are known to be abundant and enriched in CRC cases, both in tumor sites and in the peripheral blood [49]. In CRC, evidence suggests that overall, Tregs may have a negative effect on patients due to the way they suppress anti-tumor responses [7]. Studies have shown that TAA-specific Tregs have influence over T-cell response to tumors. TAA-peptides may induce Tregs to prevent T cells from performing anti-tumor actions, and it has been suggested that the use of TAAs in tumor vaccines that are unadulterated by Tregs may assist in the tumor-fighting process [50]. Chemokines released by tumors, including CCL17, CCL22, and CCL28 may “recruit” Tregs for their defense [7]. However, questions still exist as to whether or not Tregs solely have negative effects [49]. Some tumor-infiltrating FoxP3+ cells, on the contrary, seem to have a positive prognostic factor for CRC. In one study, while producing IL17, Tregs activated specific immune attacks as opposed to the expected suppression of anti-tumor activities in a mismatch repair (MMR) environment [51]. The MMR-positive setting of colon cancer may lead to the increased presence of tumor-infiltrating FoxP3+ cells and therefore be a predictor of survival, since for hepatocellular and gastric cancers ??(Figure 1) [52].
Please insert figure 1 here.
Considering the dual roles Treg cells might play in cancer, understanding where and when to inhibit Tregs is important to equip them to their full potential. In some cancers, Tregs enter the tumor environment due to the production of CCL22 by the tumor cell. Due to the inflammatory effects of CRC and, Tregs natural limitation of inflammation, it is believed that Tregs may act more as an infiltrator in CRC as opposed to other cancers [52, 53]. The increased number of Treg cells has varying prognostic indications [54]. Conflicting results over whether or not T regs actually provide benefits to cancer patients has led to debate. It has been theorized that when T cells drive the immune response, Tregs generally are more present and active in offense against T-cells, whereas when inflammatory cells drive the immune system, Tregs act as assistants to these cells [55]. Tregs are universally accepted as supporting an anti-immune response environment, but new research on inflammation and its effects are quietly challenging that sentiment.
There are two classifications of Treg cells: natural nTreg cells, which come straight from the thymus and induced iTreg cells, which arrive upon the interaction of CD4+ T cells with antigen presenting cells (APCs) [55]. Within some cancers, like renal carcinomas, only nTreg cells are present, based on the detection of both FoxP3+ and Helios, the latter of which is not present in iTreg cells. Both are known to play critical roles in subduing anti-tumor immune response.
Currently, research on targeting Treg cells and slowing their progression has been underway [49]. One study found that the inhibition of the vascular endothelial growth factor receptor(VEGFR) pathway in mice allowed for the cessation of excess Treg proliferation, restoring the Treg population to its normal numbers [54]. Immunotherapies using Treg cells have been in the works for several years, and a strong base for Treg research has been built, albeit for non-CRC diseases [44, 45, 56-59]. For the most part, resources are mostly devoted to reducing Tregs. Mast cells (MC) have been found to transform Treg cells anti-inflammatory processes into pro-inflammatory actions; altering MC may allow Treg cells to attack CRC inflammation more effectively [56-59].
CRC and Responses of Natural Killer Cells
Natural Killer (NK) cells are lymphocytes that can directly kill target cells without prior activation which are detrimental to the host [60]. They are especially critical in the immune system because they fight zealously against cancer [32]. The ability of NK cells to identify and eliminate the target cells (cancer cell) to make them an interest in immunotherapy.(sentence needs rewording)
NK cells are able to identify tumor cells through DNA damage signals and through cellular stress. They kill the target tumor cells several ways, including the releasing of granzyme, tumor necrosis factor-related apoptosis, effector molecules (IFN-γ and nitric oxide), and creating cellular cytotoxicity [9, 11] NK cell activation is inhibited by inhibitory receptors (KIRs and CD94/NKG2A/B) that bind to MHC-I molecules. They are activated when the MHC-I expression is downregulated under stress conditions, which causes them to lose inhibitory signaling [61]. NK cell activation is enhanced by IFNs (interferons) or Dendritic Cell/macrophage-derived cytokines [61].
After the success of genetically engineered T cells, genetically engineered NK cells are currently being researched. However, studies have shown genetically engineered NK cells have a poor efficacy in transgene delivery and NK cell apoptosis [62]. The viral transduction of NK cells is one method of genetic modification. Transduction is performed using retroviral vectors, lentiviral vectors, adenoviral vectors, or vaccinia virus vectors [62]. Although transduction enables stable transgene expression, there is a potential risk of mutagenesis and immunogenicity, a possibility of viability being compromised, and cell enrichment may be needed post-transduction. In comparison to transduction, transfection is another method with lowered regulatory problems, high efficacies, and improved viabilities. However, to induce long-term clinical responses, transfection is inadequate [62].
Tumor cells tend to develop methods that allow them to escape NK cell recognition and induce malignant NK cells [61]. Certain abnormalities in the NK cells of cancer patients have been observed, including defective activating receptors, increased proliferation of benign cells, and overexpression of inhibitory receptors [63]. Many studies targeted NK cells to improve their antitumor abilities [61]. Priming NK cells with cytokines have been shown to enhance its activity. A study showed that when NK cells were stimulated by cytokines (IL-2, 12, 15, and 18, IFN-γ and TNF-α) they became lymphokine-activated killer (LAK) cells, causing them to exhibit a higher cytotoxicity against cancerous targets However, in the cancer patients, limited antitumor effects by LAK cells were observed [62]. NK cell activators IL-12, IL-15, IL-18, and IL-21 have all been tested in cancer models in studies dealing with vaccination strategies with success [64, 65]. Autologous NK cells can be activated and expanded in vitro in the latency of IL-15 and the hormone hydrocortisone and have been shown to be effective in vivo in a lung metastasis mouse model. High doses of IL-15 were needed to see potent antitumor effects in vivo [66]. Although knowledge is limited in NK cell immunotherapy in CRC, previous studies can be used as models to guide future research in this field (Figure 2).
Please insert figure 2 here.
CRC and Role of Dendritic Cells
Dendritic Cells, or DCs, are APCs (antigen presenting cells) that help to initiate an autoimmune response to a variety of diseases such as CRC [29-32]. Immune cell responses are induced by DCs that process antigens, express lymphocyte co-stimulatory molecules, and release cytokines. DCs are also responsible for sensitizing T cells to self-antigens, reducing a number of autoimmune reactions of immune system [29-32].
DCs play a major role in anti-tumor immune responses. They are bone marrow-derived cells that gather information and deliver it to the adaptive immune system (T cells and B cells). DCs initiate immune responses by capturing antigens, presenting them in the form of antigen peptides on MHC class I molecules, and delivering them to T cells in lymphoid tissues. Non-activated DCs are immature DCs, and can effectively deliver self-antigens to T cells, introducing? immune tolerance. Activated DCs, mature DCs, can differentiate antigen-specific T cells into effector T cells. Based on environmental signals, DCs can differentiate into mature DCs that are able to initiate adaptive T cell-mediated immunity. During tumor growth, tumors typically interfere with DC maturation [67-69]. This is mediated through the secretion of IL10, causing antigen-specific energy [70-74].
DCs are potent immune cells for immunotherapy. In ex vivo generated vaccines, DCs are generated through the culturing of monocytes with cytokine combinations. These have been tested as therapeutic vaccines. Studies have found that DC-based vaccines are safe and initiate the spread of active CD4+ T cells and CD8+ T cells that will be specific to certain tumor antigens. DCs are also utilized for immunotherapy through targeting antigens to DCs in vivo. Using chimeric proteins, antigens are delivered directly to DCs. The chimeric protein consists of a DC receptor-specific antibody with a specific antigen. Studies have shown that, in vivo, specific targeting of antigens to DCs results in effective antigen-specific CD4+ and CD8+ T cell-mediated immunity [70-74].  Another method includes loading DCs on whole tumor cells, which also induces TAA-specific CD4+ and CD8+ T cell action. Research shows that murine DCs transfected with MUC1 mRNA result in MUC1-specific cytotoxic T lymphocyte (CTL) responses combatting CRC cells in vivo and in vitro [70-74].
Although there have not been many studies conducted dealing with DC immunotherapy in CRC, there has been significant research done on DC immunotherapy itself and in other major diseases [70-74]. By applying this knowledge to CRC, possible immunotherapeutic treatment in addition to the current ones may arise.
Conclusion and future perspective
In this review, we have summarized the functional role of immunobiological factors and immune cell markers in immunologic defenses against cancer.Furthermore, through recent advancements in immunology future benefits of these factors and immune cells as immunotherapeutic agents is promising. Studies demonstrating that immune suppression is not tthe entire story, thus promoting the development of CRC. The power of the immune system that protects the host from CRC development may also drive the origin of tumors when immune system compromised. The most important clinical outcome of the hypothesis is that most, if not all, the cancer that occurs in human population may have undergone through immunologic sculpting, a process of immune editing, which may results in immune escape before clinically detectable. Ultimately, immunobiological factors may play a critical role in prevention and diagnosis of CRC and other cancers; therefore, they may be used in the future treatment of cancer including CRC.
This work, in part or fully supported by the National Institutes of Health grants P20CA192976 (MKM) and P20CA192973 (UM); Cancer Biology Research and Training.
Conflict of Interest
The authors declare there is no conflict of interest regarding the publication of this paper.
Author’s Contribution
Sanjay Kumar, Jacob Mesina, Vandana Macha, and Kayla Pressley were responsible for data collection, literature review and writing. The concept, development of the review article, including the process and each section of the paper,corrections, and modifications was under the supervision of Drs. Sabita Saldanha and Manoj Mishra.
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Figure and figure legends

Figure 1. Role of various immune cells in colorectal cancer progression. Tumor cell produce several cytokines and chemokines to suppress the function of various immune cells. These cytokines/chemokines recruit regulatory T cells. High number of regulatory ???in colorectal tumor microenvironment leads to the suppression of effector T cell, NK cells, and NKT??? cells (not shown in figure) that may facilitate tumor growth and progression. [1]. T cell directly sensitizing cancer cells; [2] T cells with APCs targeting cancer cells; [3] NK cells releasing cytokines and granzyme to suppress tumor promotion; [4] Tumor cell producing cytokines/chemokines which induced the number of Treg in the tumor microenvironment result in the suppression of other immune cells such as CD4+ and cytotoxic CD8+ T lymphocytes.

Figure 2. Role of T-regulatory cells in non-inflammatory environments vs inflammatory environments. [1]. Tumor initiation evokes an inflammatory response that recruits various types of immune cell including T cells. These cells fight against inflammation by producing several types of cytokines and chemokines that help in the suppression/removal of the inflammatory response. [2]. Contradictory to this, cancer cell produce cytokines/chemokines that recruits T regulatory cell. High number of regulatory??? in colorectal tumor microenvironment leads to the suppression of effector T cell that may facilitate tumor growth and progression.

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