The immune elimination phase of cancer immunoediting is sine qua non of the original immunosurveillance process. It envisages the destruction or eradication of cancer by the host immune system and is believed to occur when a cell gets transformed by overcoming its intrinsic tumor suppressor mechanisms, before being able to establish a full-blown tumor. Although the existence of such a phenomenon has been hypothesized since long, the early experiments carried out on nude mice models which are only partially immunodeficient failed to prove it. The definitive experimental proof to its presence came from the work of Shankaran et al. in the last decade (Table 12.1, Fig. 12.2) [6]. However, despite the experimental evidence of its presence in mice, it has been difficult to demonstrate it in the clinical scenario. Still, the data obtained from various cancer registries wherein a higher cancer incidence especially of viral etiology has been observed in immunosuppressed transplant recipients suggests its existence in human subjects as well. Currently, a similar trend has been noticed in the setting of acquired immunodeficiency syndrome [13,14]. The proponents of this stage in cancer immunity state that many of the cell transformation events occurring in our body may be removed quietly by the immune system without us ever being aware about it. Spontaneous regression has been reported in some tumors including cutaneous melanoma, retinoblastoma, osteosarcoma, etc., in humans [15]. Studies have shown that both innate as well as adaptive immune response contribute to fighting off the cancer from our body.

This phase represents an intermediate stage of immune response in cancer. During this phase, the cancer and the immune system both coexist without allowing each other to dominate. The immune system cannot eliminate the cancer during this phase; however, it does not allow it to expand or metastasize. The cancer in turn is sculpted by the immune system, thus leading to the emergence of variants resistant to the immunological attack [3].

Various studies in mice have pointed toward the occurrence of the equilibrium phase in cancer immunity. In experiments on MCA-induced tumors in mice, Koebel et al. demonstrated the presence of inert lesions in healthy mice, which grew when subjected to immunological oppression (Fig. 12.4) [23]. The study served to be an important milestone in proving the existence of the equilibrium phase in cancers. Likewise, the tumors have been observed to stay dormant for decades after remission in human cancer patients, which is believed to be due to the fact that immune system keeps them in check. The immune system is believed to synergize with chemoradiotherapy in treatment-induced remission which renders the tumors silent. However, they relapse promptly after any kind of immune insult, thereby, further proving the presence of immune dormancy. The minimal residual disease commonly observed in hematological malignancies and the emerging donor-derived malignancies in immunosuppressed transplant recipients are considered two examples of the equilibrium phase in humans. Even though the immune system prevents monoclonal gammopathy of unknown significance (MGUS) from progressing to myeloma, it fails to eliminate the MGUS cells [24,25].

Adoptive T cells, both CD4⁺ and CD8⁺, have been observed to play a pivotal role in cancer immune equilibrium. Immune-sufficient mice with inert tumors are shown to develop into full-fledged tumors only upon depletion of T cells/IFN-γ/IL-12. However, the depletion of innate immune cells was not found to result in the development of tumors. Moreover, tumor cells were found to be highly immunogenic during the equilibrium phase, as they are unedited by the immune system and become less immunogenic at the end of this phase [23,26,27].

In addition, the mechanisms including cellular and angiogenic dormancy also complement the immune system in maintaining cancer cells in the dormant state. In the former, the tumor cells hide themselves in specialized niches, become quiescent, and wait for the opportunity to regrow. In the later condition, expansion is not possible, due to the lack of adequate vascularization. When faced with favorable conditions, tumor cells come out of their slumber and undergo a series of genetic and epigenetic modifications which increase their immune resistance, eventually leading to the next phase of cancer immunity, known as immune escape. Studies are being conducted to identify the genetic and molecular signatures of dormant tumor cells which allow them to retain their dormant status or facilitate their escape [23,26–29].

The escape phase represents the final and most extensively studied phase of the immunoediting process. The unleashing of mechanisms underlying the escape phase has formed the basis for the development of various therapeutic agents with the aim to stop the progress of the neoplastic process. Due to increasing genomic instability, cancer cells acquire various characteristics enabling them to ward off the immune process or to modify it in such a way which is beneficial to tumor cells. Tumors utilize a number of strategies to evade an effective immune response (Fig. 12.5). The basis of an effective immune response against any Ag is its recognition as a nonself and its presentation to immune effector cells. Tumors escape recognition by either presenting self Ags to which the immune system is already tolerized or by modulating their antigenicity. The later involves the shedding of tumor Ags into the circulation from where they may be removed [30]. The next line of defense adopted by tumor cells is the modulation of APCs, rendering them incapable of effectively presenting cancer Ags to immune cells. The APCs like DCs are either deleted or functionally compromised in response to the factors secreted by malignant cells [31]. Tumor-induced co-inhibition of the second signal of the Ag presentation and consequent immunosuppression has now been recognized in several cancer types [32]. In addition, the tumors alter MHC molecules especially MHC class I and other components of Ag processing machinery in the APCs, so as to further incapacitate the presentation of its Ags to the immune system [33]. Besides, tumor cells plunge into an active battle against the immune process by attacking its adoptive and innate immune cells. Tumor cells subvert T cells and render them anergic through co-inhibitory molecules including cytotoxic T-lymphocyte antigen-4 (CTLA-4) and PD-L1 [34]. Anergic T cells are unable to produce cytokines such as IL-2 and IFN-γ. Therefore, the autocrine and paracrine activation of CD4⁺ cells and other immune cells including B cells, macrophages, and CD8⁺ cells are blocked, leading to further suppression of the immune cascade [35]. Moreover, tumors also express Fas ligands on T cells, leading to lymphocyte apoptosis [36]. Not only do they suppress CD4⁺ and CD8⁺ cells, but also promote the suppressor T-cell phenotype such as CD25⁺Foxp3⁺ T-regulatory cells. These cells secrete IL-10, TGF-β, and VEGF which suppress the antitumor response and promote tumoral angiogenesis (Table 12.2) [37]. Besides, tumors also inhibit innate immune response by induction of quantitative and qualitative defects in NK cells, macrophages, and neutrophils. NK cells have been found to exhibit decreased cytotoxic potentiality due to the presence of tumor-secreted factors including TGF-β in the tumor microenvironment (TME) [38]. The later along with other cytokines (IL-4, IL-13, etc.) present in the tumor bed favors the accumulation of M2 macrophages, which also induce immunosuppression [39]. Recruitment of immature myeloid cells like myeloid-derived suppressor cells (MDSCs) further complements the tumor-immunodeficient environment by reducing T-cell and NK-cell activation and promoting neovascularization via factors like VEGF [40].

Other mechanisms such as anaerobic glycolysis, hypoxia, and acidity of the TME along with the existent defects in tryptophan metabolism induced by increased expression of the enzyme indoleamine 2,3-dioxygenase (IDO) further depress the antitumor immunity, thereby leading to cancer progression and metastasis [41–43].

Antigenicity of tumors has always been a matter of discussion. In the past, it was believed that since tumors are derived from self cells, the immune system is more receptive to their Ags. However, it was subsequently noticed that tumors may express Ags which are quantitatively or qualitatively different from self Ags, thus rendering them sensitive to the immune attack. Quantitative differences include significantly increased expression of Ags, which are less expressed in normal or benign conditions or reexpression of Ags only expressed at a specific stage of embryonic development (Table 12.3). Moreover, the lineage-specific Ags expressed normally in specific tissues may be expressed aberrantly in tumor cells. Qualitative differences are produced due to mutational events occurring during carcinogenesis. Over the years, several efforts have been made for the identification and mapping of the Ags expressed on tumor cells; various nomenclatures have been used to characterize them such as tumor-associated Ags and tumor-specific Ags. Antigens capable of evoking a tumor-specific immune response have also been designated as tumor rejection Ags in some textbooks, e.g., tyrosinase, MUC-1, Her-2/neu, β-catenin, caspase-8, etc. [44]. Previous studies on tumor antigens (TAs) have mainly focused on the discovery of new Ags and their classification into two subclasses, a group which can evoke a protective immune response and another group serving as potential therapeutic targets. However, the advent of cancer immunoediting theory has changed our insight on TAs, as they are now considered to be one of the prime targets of the above process. Currently, ongoing studies are attempting to differentiate between the antigenicity of the original or unedited tumors and those sculpted by the immune system [17,45,46]. Differences between the immunogenicity of tumors derived from carcinogen MCA (more immunogenic) and those arising spontaneously (less immunogenic) in mice have been described by DuPage et al. [47]. They also showed that primary sarcomas are edited by the immune system and, hence, become less immunogenic in order to escape the T-cell response. In the same line, Matsushita et al. obtained similar results in their study on tumor exomes [48]. A recent study has revealed the presence of antiinflammatory antibodies to tumor-associated Ags like NY-ESO-1, thereby suggesting the importance of humoral immune system in cancer immunoediting [49]. Novel genetic-based approaches including exome sequencing, in silico analysis, and CD8⁺ T-cell cloning are likely to further help in understanding the alterations in tumor antigenicity occurring during different phases of cancer immunity [48].