Introduction

Although cancer is generally characterised as group of cells that have acquired the ability to grow uncontrollably, certain alterations in cell physiology dictate whether or not a cell become transformed into malignant growth. These essential alterations identified as self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, evasion of programmed cell death, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis are collectively referred to as the hallmarks of cancer and were first described in 2000 by Hanahan and Weinberg [1]. A decade following their initial publication and due to intensive cancer research, the duo revisited the hallmarks of cancer, this time adding two emerging hallmarks (deregulating cellular energetics and avoiding immune destruction) and two enabling characteristics (genome instability and mutation, and tumour-promoting inflammation) to the roster, while concomitantly giving recent research updates to the previously described hallmarks [2]. These hallmarks are summarised and depicted in Figure 1 below together with specific therapeutic targeting strategies.

The roles that the immune system plays in preventing formation of incipient neoplasias and in eradicating late-stage tumours and micrometastasis as well as its role in promoting tumour formation were clarified in the second publication of the hallmarks of cancer [2]. We now know that there is a crosstalk between the immune system and incipient cancer cells, the tumour they form and their micrometastases, and that these intimate interactions could inhibit or promote tumour growth, development and metastasis [2, 3].

In order to proliferate, survive and become a clinically detectable tumour, cancer cells must have to devise strategies to evade the immunosurveillance imposed by the immune system. Consequently, considerable efforts have been made in our understanding of how cancer cells evade immune destruction, which has given insights into how to specifically target cancer cells using our body’s natural defenses; a field that is broadly classified as cancer immunotherapy. This essay will attempt to explain why immune evasion by cancer cells, relative to other hallmarks of cancer, is the most important hallmark for cancer biology. In addition, it will provide insights into the mechanisms employed by cancer cells to evade immunosurveillance and finally attempt to discuss the various cancer immunotherapeutic approaches that have been used in the treatment of cancer.

Reasons why immune evasion by cancer cells is an important hallmark of cancer biology relative to other cancer hallmarks

All of the hallmarks of cancer as alluded to above are equally important for the development and progression of cancer. For example, in order to become transformed, a cell or groups of cells must acquire the ability to sustain chronic proliferation by deregulating growth-promoting signals that control their entry into and progression through the cell division cycle [1, 2, 4]. This is largely driven by the ability of cancer cells to overexpress their own growth factors, while simultaneously responding to the same growth factors by expressing their cognate receptors in a paracrine or autocrine fashion [5]. As well as sustaining proliferative signalling, cancer cells must also acquire the ability to evade growth suppressors. This is achieved by inactivating tumour suppressor genes that would otherwise function to limit cell growth and proliferation [2]. For example, by inactivating the retinoblastoma (RB) tumour suppressor pathway, cancer cells are able to proliferate uncontrollably [6]. While the preceding hallmarks together with the ones mentioned in the introduction paragraph above contribute to the cancer phenotypes, evading immune destruction is one challenge that the incipient cancer cells must overcome [2]. This essay, therefore, considers immune evasion as the most important and critical hallmark of cancer biology due to the following factors and/or reasons. Having acquired the ability to proliferate uncontrollably and evade growth suppressors and resist cell death via loss of tumour suppressor proteins, cancer cells must also devise strategies to avoid immune destruction. If cancer cells were unable to avoid immune destruction even after acquiring all of the other hallmark characteristics, the immune system would have been able to selectively target and destroy them even before they are clinically detectable. This is because the increased genetic instability (leading to increased mutational burden) within cancer cells leads to generation of tumour-specific antigens (neoantigens) that eventually become sensed by the innate immune system leading to tumour detection and rejection by the immune system [7-9]. Moreover, the immune system has long been known to play important role in tumour growth and control. This is backed up by the fact that immunocompromised individuals are at higher risk of having cancer, and that spontaneous regression of some tumours is possible, although in very rare cancer cases [10-12]. This idea of the involvement of the body’s natural defense system to fight off cancer also stems from the effective use of the bacterium Bacillus Calmette-Guérin (BCG) in treating bladder cancer back in 1976 [13]. Moreover, current immunotherapies, especially immune checkpoint inhibitors, have demonstrated improved patient outcome for multiple solid and haematologic malignancies [14], highlighting an important role of the immune system in suppressing cancer growth. Lastly, compared to other cancer therapies, the immunological memory of the adaptive arm of the immune system together with their ability to detect and eradicate tumour variants as they emerge makes the immune system a very useful biological cancer therapeutic tool to exploit [15]. Hence, in an ideal situation, our immune system would have been able to eradicate cancer cells. However, cancer cells adopt strategies to evade immune response by promoting immunosuppressive signals, which lead to their own growth advantage [16, 17]. In summary, immune evasion by cancer cells represents an important hallmark for cancer biology since without attack by the immune system, cancer cells would continue to grow, divide and metastasize. The next section of this essay will attempt to explain the complex interactions between the immune system and the developing cancer cells

At the crosstalk between cancer cells and the immune system

During the process of cancer development, progression and metastasis, the immune system interacts intimately with both the cancer cells and the normal stromal cells, a complex crosstalk that can both suppress and enhance the growth of the tumour [18, 19]. For a tumour to be clinically detectable, it must devise strategies to evade the immunosurveillance techniques employed by the immune system. The adaptive arm of the immune system uses its CD8⁺ cytotoxic T-cells and CD4⁺ helper T-cells to target a developing neoplasia for eradication by the production of cytokines such as interferon gamma (IFN-g) [3, 20]. Moreover, the cytotoxic effects of CD8⁺ T-cells also contribute majorly to the killing of tumour cells [21]. Cross-priming and activation of the adaptive arm of the immune system above is dependent on antigen presentation by professional antigen presenting cells (APCs), such as dendritic cells (DCs), which are a part of the innate immune response [22-25]. However, there are reports to show that APCs may be dysfunctional in tumour-bearing animals due to production of immunosuppressive factors by tumours that prevent CD34⁺ stem cell maturation into DCs [26-28]. This and other factors contribute to immune evasion strategies employed by cancer cells, which the next section describes.

Mechanisms of immune evasion

Despite the barriers imposed by both the innate and adaptive arms of the immune system as described above, cancer cells are still able to subvert their host’s anti-tumour immune responses to become clinically detectable. Certain characteristics of the tumours as well as the stromal and chronic inflammatory cells contribute to the eventual escape of the developing tumour [29]. As well as suppressing tumour growth, the immune system can also select for tumours with decreased immunogenicity, thereby enhancing tumour growth [18]. This is explained by the concept of cancer immunoediting, a major escape strategy employed by developing cancer cells to avoid immune-mediated elimination [30-32]. Three separate phases of immunoediting is widely accepted: elimination, equilibrium and escape.  Elimination is the state where both the innate and adaptive immune systems detect and kill the most immunologically vulnerable developing cancer cells that characteristically express tumour antigens. However due to heterogeneity between individual cancer cells, orchestrated by genetic instability, a subset of cancer cells with reduced immunogenicity can remain dormant for years as suggested by experimental models [33]. During this time, the cancer cells continue to divide, and acquire additional mutations in response to immune-induced inflammation or by chance. This stage, where there is a balance between new tumour cell variants and elimination by the immune system, is termed ‘’equilibrium’’. Ultimately, tumour cells are able to subvert immunosurveillance through mechanisms such as loss of tumour antigens, increased resistance to attack by immune cells [34], or by recruitment of immunosuppressive cells to the tumour microenvironment (TME) [35, 36]. This stage represents how tumour cells escape the immune system and become a clinically overt tumour. A schematic view of immunoediting is depicted in Figure 2 below. These myriad of escape strategies are explained further below.

To ensure they continue to survive and escape immune surveillance, tumours recruit immunosuppressive thymus-derived CD4⁺CD25⁺FoxP3⁺ regulatory T-cells (Treg) via production and secretion of certain chemokines [37, 38]. Treg-mediated immunosuppression is considered a major strategy utilised by tumours to escape destruction and it presents a major obstacle to the success of immunotherapy [39-41]. CTLA4-mediated induction of indoleamine 2,3-dioxygenase-expressing APCs (which degrades tryptophan required for T-cell activation)[42] and perforin and granzyme A pathway activation [43] are some of the suppressive mechanisms adopted by Treg cells to mediate killing of CD8⁺ T-cells and APCs. These and other Treg-mediated mechanisms of immune suppression are summarised in Figure 3 below. In addition, myeloid cells, such as myeloid-derived suppressor cells (MDSCs), modulated DCs and M2 macrophages can form an inflammatory microenvironment to promote tumour initiation, angiogenesis and metastasis [44, 45]. Secretion of immunosuppressive cytokines (including IL-4, IL-6 and IL-10), generation of nitric oxide (NO) and reactive oxygen species together with increased activity of L-arginase have been suggested as some of the mechanisms of immunosuppression by myeloid cells [44, 46]. For example, production of IL-10 correlates with the induction of T-cell anergy and is regarded as a major immunosuppressive factor released by tumour cells, together with TGF-b [47].  The above findings indicate that although some tumours may retain their antigenicity and immunogenicity, which are targets of effector T-cells, they can still evade immune elimination by promoting an immunosuppressive microenvironment.

Defective antigen presentation represents another mechanism that tumours utilise to escape immune surveillance. A variety of mutated and nonmutated antigens with the potential to induce an immune response against the tumour are [over]expressed on the surface of cancer cells [48]. In an attempt to evade immune destruction, cancer cells downregulate antigen processing and presentation machinery (APM) that control the major histocompatibility complex  (MHC)-I pathway and other related proteins [49-52]. This leads to reduced tumour cell surface antigen presentation which prevents cytotoxic T-cells from recognising target antigens on tumour cells, thus promoting tumour growth and metastasis. In addition, tumours are able to induce T-cell tolerance by their failure to express co-stimulatory molecules which leads to T-cell anergy [53]. In the same vein, tumours can also undergo immune deviation by shifting the balance from the anti-tumour Th1 response to  the tumour-promoting Th2 response, a process that is TGF-b and IL-10-dependent [54]. Moreover, tumours that possess sufficient antigenicity are still able to subvert the immune response by upregulating the inhibitory molecule programmed death (PD)-L1 on their cell surface [55], whose receptors are known to be significantly upregulated on T-cells that infiltrate the tumour [56, 57].  This suggests tumours may use these PD-1/PD-L-1 signalling pathway to negatively regulate an immune response against it. Consequently, tumours overexpressing PD-L1, including oesophageal, kidney, ovarian and pancreatic cancers, are associated with poor prognosis [58-61]. Thus, cancer cells can induce T-cell tolerance and immune deviation by dysregulating certain pathway and/or upregulating immune-inhibitory molecules on their cell surface. These upregulated molecules also present a better avenue to develop agents or antibodies that specifically target and inhibit them, as will be discussed below.

Solid tumours also evade immune destruction by excluding T-cells. A higher immunoscore, which is dependent on increased T-cell infiltration, correlates with good prognosis for patients. This T-cell infiltration is dependent on certain chemokines (e.g., CXCL9 and CXCL10) and cytokines expressed on the surfaces of tumour cells or within the TME [62, 63], which serve as ligands for chemokine receptors on the surface of T-cells [64]. Tumours can, however, exclude anti-tumour T-cells from the TME by downregulating the ligands for chemokine receptors expressed on T-cells via epigenetic silencing as recently observed in ovarian cancer [65]. In addition, tumours can also exclude T-cells by expressing FasL, which induces apoptosis in T-cells expressing its cognate Fas receptor [66]. Lastly, certain oncogenic mutations within tumours indirectly modulate the TME by interfering with immunity. For example, Kras mutations induce the expression of granulocyte macrophage colony-stimulating factor (GM-CSF), which in turn recruit myeloid cells leading to reduced CD8⁺ T-cell infiltration in pancreatic ductal adenocarcinoma [67, 68].

The above tumour and stromal cell-mediated processes illustrate the complex mechanisms that act in concert to orchestrate immune evasion by cancer cells. Figure 4 below is an overview of some of the immune evasion strategies highlighted above as well as other evasion strategies not described above due to space limitation. The next section will discuss strategies that have been exploited to boost host immune response against tumours.

Therapeutic strategies to targeting immune evasion by cancer cells

As noted above, the link between the immune system and control of cancer growth was already established decades ago and became even more relevant due to advances in research that eventually gave birth to cancer immunotherapy as an arm of cancer therapy. The overall goal of cancer immunotherapy is to use the host immune system to eradicate cancer by exploiting specific evasion strategies devised by cancer cells [14]. The field of cancer immunotherapy encompasses many therapeutic strategies, including use of checkpoint inhibitors, oncolytic viruses, adoptive cell therapies, and biologic modifiers such as cytokines and vaccines to augment tumour immunity [69, 70]. Some of these are explained below.

The immune checkpoint inhibitors (ICI) are monoclonal antibodies that promote immune-mediated elimination of tumours by interrupting co-inhibitory signalling pathways [71]. The first approved ICI, ipilimumab, prevents T-cell inhibition by targeting CTLA-4 in patients with advanced melanoma [72, 73]. The PD-1 ICIs, pembrolizumab and nivolumab have also shown significant improvements in the treatment of patients with melanoma and non-small cell lung cancer [74-76]. In the same vein, Atezolizumab (anti-PD-L1) was approved in 2016 for the treatment of melanoma, bladder and lung cancers together with triple-negative breast cancer as at March 2019 [77-79]. The clinical efficacies of these ICI as well as others are currently being investigated for other tumours as shown in Table 1 below (see attached document). These therapies are used as single agent or in combination. For example, combined administration of ipilimumab and nivolumab showed at least 80% tumour regression in 50% of patients with advanced melanoma in a phase I clinical trial [80]. Although very efficacious, combination therapy of ICIs or with other conventional therapies can lead to more side effects and toxicities [14]. In addition, although these ICIs have shown improved outcome, only a subset of patients benefit from them with some patients experiencing severe immune-related adverse events due to various local and systemic immune responses [14, 81]. This demonstrate the importance of using predictive biomarkers to identify patients who will eventually benefit from the treatment to avoid any adverse effects.

Another type of immunotherapy that has been of keen interest to oncologists and cancer researchers is therapeutic cancer vaccines. By increasing tumour antigen presentation, cancer vaccines can augment the anti-tumour response of the immune system [82]. They are broadly divided into two: autologous and allogenic cancer vaccines [82]. The first FDA-approved autologous cancer vaccine, sipuleucel-T, was used for the treatment of castration-resistant prostate cancer [83]. Here, DCs are collected from the patients and exposed to GM-CSF before being reinjected into the patient’s circulation. Although sipuleucel-T was shown to extend survival of patients in clinical trials, it had no effect on disease progression in the clinical setting [83]. Despite the potential promises of cancer vaccines, there are many hurdles yet to be overcome, including specific tumour-dependent antigen identification, improving their therapeutic efficacies, delivery and enrichment within the tumour relative to normal tissues [70]. The ideal vaccine should be able to trigger DC maturation and subsequent priming and activation of CD8⁺ T-cells. Why these obstacles are likely to be circumvented, the efficacy of cancer vaccines may still be compromised by the cancer cells’ ability to evade the immune system via downregulation of their antigen presentation pathways. As noted above, this highlights the importance of using predictive biomarkers to identify patients who are likely to benefit from this type of therapy based on how antigenic and immunogenic their tumours are.

In addition to the above types of immunotherapies, adoptive T-cell therapy (ACT), which involves isolation and in vitro modification and expansion of patient’s own T-cells and subsequent re-injection into the patient, is also promising [82]. A specific example of ACT is chimeric antigen receptor T-cell therapy (CAR-T) which uses T-cells that have been engineered in vitro to specifically target and eradicate the tumour [69, 82]. Although CAR-T therapy has demonstrated dramatic clinical responses, it is not without problems, such as cytokine release syndrome experienced by patients [69]. CAR-T was first approved for use in children with relapsed B-cell acute lymphoblastic leukemia  in 2017 and later for lymphomas [84, 85]. These and other immunotherapeutic approaches, including use of biologics, such as cytokines, are represented in Table 2 below (see attached document) together with the basic mechanisms, and the major advantages and disadvantages of each therapeutic approach.

Conclusions

The important roles that the immune system plays in eradicating cancer has been the focus of this essay. However, as well as suppressing cancer, some cells of the immune system have been implicated in the development and progression of cancer. By secreting various factors that modulate the tumour microenvironment and due to high intra-tumoural heterogeneity, tumours are able to evade the immune surveillance, grow, form new blood vessels, metastasize and exhibit their clinical manifestations. This essay has attempted to describe majority of the strategies adopted by developing cancer cells and the tumour they eventually form in evading the immune response. The various evasion strategies have been exploited by research scientists in order to boost the immune system. Among the many cancer immunotherapeutic strategies, ICIs have received the most attention as they have so far improved patients’ outcome. Again, the impact of ICIs was also reflected when both Professors James P. Allison and Tasuku Honjo were jointly awarded the Nobel Prize in Medicine or physiology in 2018 for their seminal work that led to our understanding of how the immune system fights off cancer. Although this essay has attempted to show evidence that immune evasion by cancer cells represents an important hallmark for cancer biology, and that developing drugs to boost the immune system has had some clinical benefits, there are still some challenges to be overcome as highlighted under immunotherapeutic strategies against cancer cells above. Despite these obstacles, the potential promises of cancer immunotherapy to people living with cancer is enormous.

 

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