Collectively, the role of these innate and adaptive immune responses in oncogenesis serves to be the underlying basis for immune surveillance and cancer immunoediting [ 4 , 40 ]. The role of the immune system in cancer pathogenesis has been a subject of great interest and debate for many decades due to its ability to mediate protection against cancer and promote cancer progression [ 4 , 40 ]. The role of immune responses in the context of cancer biology is commonly referred to as cancer immunosurveillance [ 4 , 40 ].
Due to these and other inconsistent reports from studies highlighting the immunosurveillance mechanisms in cancer, the concept was largely rejected [ 4 ]. However, with the scientific advancement in genetically modified animal models, design of studies to investigate immunosurveillance was feasible [ 4 , 40 ]. Consequently, the role of immunity in cancer was reevaluated once again in the s [ 4 , 40 ].
Notably, studies from these and other animal models deficient in some form of the immune response were highly indicative of immunity protecting against carcinogenesis and tumor formation [ 4 , 40 ]. Moreover, immune-mediated protection against cancer is not just limited to animal models, rather it has become increasingly clear that immunosurveillance is clinically observed in humans as well [ 40 ].
Interestingly, recent reports suggest that a delicate balance between cancer dormancy and progression exists and this balance is the foundation for the principle in oncology known as immunoediting [ 52 ]. Three major phases that comprise the immunoediting process in cancer pathogenesis are elimination, equilibrium, and escape Figure 2 , [ 4 , 40 ]. These underlying immune responses of immunoediting help shape the immunogenicity of various cancers.
The outcome of immunoediting may be attributed to factors which include the temporal or spatial location of the cancer, molecular mechanisms involved in transformation from normal to transformed cells, and the inherent genetic factors of the immune system [ 52 ]. The elimination phase of the immunoediting process is a component of the cancer immunosurveillance theory and refers to the ability of the innate and adaptive immune system to recognize and eradicate cancer cells Figure 2 [ 4 , 40 , 53 ].
Mechanisms by which cancer cell lysis occurs are via secretion of perforin from cytolytic immune cells i. The equilibrium phase focuses on the dynamic state of the cancer cells to negatively regulate the immune system leading to a block in the elimination phase of immunoediting and a transition to the equilibrium phase Figure 2 , [ 4 , 40 , 53 ]. In the equilibrium phase, immune responses are still active against the tumor; immune cells help regulate and control cancer growth or metastasis while keeping it in the latent dormant state.
The phase of equilibrium is considered to be the longest phase in the immunoediting process [ 4 , 40 , 53 ]. Despite these control checkpoints that are modulated by the immune system, the heterogeneity and genetic variations in cancer enable them to acquire the ability to become immune-evasive and escape the equilibrium state to expand and become detrimental to the host [ 4 , 40 , 53 ]. This escape phase is mediated through several immunosuppressive mechanisms one of which includes downregulation or aberrant expression of MHC class I on the cancer cell surface protecting it from cytotoxic effector functions of immune cells in the innate and adaptive immunity Figure 2 [ 39 , 54 ].
Multiple mechanisms such as suppression of tumor antigen expression, induction of antiapoptotic pathways to prevent cytotoxicity, and cancer-induced immunosuppression aid in the escape of cancer cells from the elimination and equilibrium phases of immunity [ 4 , 40 , 53 ]. Notably, it is this escape of cancer cells from immunity and the mechanisms involved in this escape that has been the driving force of investigations focused on the immune-oncology paradigm.
Gaining a detailed understanding of immunoediting process in cancers will be critical for development of immunotherapies for cancer treatments. Precision medicine, a novel approach for patient-specific therapies, is revolutionizing clinical outcomes and standard of care [ 55 , 56 ]. Therefore, in efforts to treat various forms of cancers, scientific advances have been made towards developing therapies that exploit the immune system [ 55 ].
These specific types of cancer treatments that focus on utilizing innate and adaptive immunity are referred to as cancer immunotherapies [ 55 ]. Due to the paradigm shift in health care which focuses on precision medicine, more initiative is directed towards establishing immunotherapy-based personalized treatments towards individual cancer patients.
These cancer immunotherapies can be classified into several different categories: vaccines, monoclonal antibodies, recombinant cytokines, small molecules, and autologous T cells [ 55 ]. The site, the type, and the stage that the specific cancer is in dictate the type of therapy that is best suited for the patient. Several FDA approved and clinical trial immunotherapies have been developed to treat various forms of cancer [ 55 ]. Despite the initial promising success rates of these therapies, the vast majority of patients relapse [ 56 ]. These cancers harbor subset of genetic mutations that may result in distinct molecular characteristics, thus giving rise to the possibility of predictive biomarkers for potential therapies.
Identifying such genetic mutations may result in identification of predictive immune molecular signatures or immune biomarkers cancer-specific neoantigens among individual cancer patients which is a key step in developing patient-specific immunotherapies [ 55 ]. Interestingly, by evaluating specific genetic mutations the patient-specific cancer causing determinants can be identified and appropriately treated. To date, several immunotherapies have been developed to treat cancers.
While some of the treatments are already on the market or have been approved for clinical phase trials, through the use of high-throughput sequencing technologies, multiple genetic mutations can be identified to develop personalized treatments [ 56 ], thereby highlighting the importance of exploiting single-agent versus combination therapies in personalized cancer treatment plans [ 56 ].
The subsequent section in this review focuses on available immunotherapies for various cancers. However, it is important to note that through precision medicine efficacy of immunotherapies and cancer-related clinical outcomes can be improved by identifying and targeting patient-specific tumor antigens [ 55 , 56 ]. Various cancers have unique triggers that result in their escape from the immune response making them more resistant to immunity [ 4 ].
Therefore, in efforts to treat various forms of cancers, scientific advances have been made towards developing therapies that exploit the immune system [ 40 ]. The specific types of treatments that focus on utilizing innate and adaptive immunity in oncology are referred to as cancer immunotherapies [ 54 ]. Cancer immunotherapies can be classified into several different categories: vaccines, monoclonal antibodies, recombinant cytokines, small molecules, and autologous T cells [ 1 ].
Depending on the location, cancer type, and the stage that the specific cancer is in, the type of therapy that is best suited for the patient is dictated. It is a form of autologous cellular immunotherapy that consists of peripheral blood mononuclear cells, cytokine granulocyte macrophage colony stimulating factor GM-CSF , and immunosurveillance of the tumor antigen-prostatic acid phosphatase PAP [ 54 , 57 ]. The mechanism of action involves the uptake of PAP by APCs which is presented to T cells for activation, differentiation, and initiation of their effector functions [ 57 ].
Some cancers, such as cervical cancers, arise from oncoviruses like human papilloma virus HPV ; therefore vaccinations against these oncoviruses can be incorrectly classified as vaccines against cancer [ 59 ].
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Monoclonal antibodies are also used as cancer immunotherapies [ 60 ]. In March , Ipilimumab was FDA approved for treatment of metastatic melanoma malignant skin cancer. It is a monoclonal antibody targeting CTLA4 on T cells [ 54 ]; thereby it inhibits the suppressive effects of CTLA4 on T cells and allows activation of T cells for immune responses against specific cancers Figure 3 [ 54 ].
Notably, Ipilimumab is also known to inhibit the immunosuppressive function of Tregs [ 54 ]. Similarly, IgG4 monoclonal antibody against PD-1 Keytruda has been on the market for treatment of melanoma patients Figure 3 [ 61 ]. PD-1 is expressed on T cells and plays a role in immune-suppression by repressing T cell activation.
However treatment with Keytruda prevents the inhibitory effects of PD-1 on T cells, thereby, allowing activation of T cells and immune responses against melanoma [ 61 ]. Similarly, Nivolumab is an FDA approved IgG4 monoclonal antibody that targets anti-PD1 in melanoma and squamous non-small-cell lung cancer patients [ 61 ]. It functions in the same manner as Keytruda [ 61 ]. In recent years, biotech companies such as Genentech have made efforts in developing potential monoclonal antibodies against the ligand for PD-1, PD-L1, as another mechanism to activate T cell-mediated immune responses and inhibit the immune-suppressive mechanisms of PD-1 in certain cancers [ 39 ].
There are also monoclonal antibodies conjugated to chemotherapy drugs or radioactive particles [ 62 ]. Interestingly, monoclonal antibody immunotherapy targeting two different proteins simultaneously has also been developed and approved by FDA. This drug is known as Blincyto and it is a monoclonal antibody where one part attaches to CD19 on B cells and the other part of the antibody attaches to CD3 on T cells for T cell activation [ 63 ]. The CD19 cell surface marker assembles into a complex with other markers such as CD81 and CD21 complement receptor to lower the threshold for B cell activation [ 64 ].
In this manner, the normal T cells can recognize and mediate cytotoxicity on the cancerous B cells in efforts to eradicate them [ 63 ]. Another immunotherapeutic approach for cancer treatments involves the use of recombinant cytokines or small molecules. For example, Proleukin is an FDA approved recombinant IL-2 cytokine for treatment of renal cancer and melanoma patients Figure 3 [ 54 ].
This mechanism of action centers around the ability of IL-2 to promote T cell activation and the activation of other immune cells lymphocytes that express IL-2 receptors [ 47 , 65 ]. Sylatron is comprised of IFN- 2b conjugated to polyethylene glycol [ 66 ]. The polyethylene glycol reduces the immunogenicity of IFN- 2b by concealing it from the immune system until it reaches its target [ 66 ]. Recombinant G-CSF, known as Filgrastim, has also been approved and been on the market to treat neutropenia in patients with certain forms of leukemia Figure 3 [ 67 ].
Recombinant human G-CSF can bind to its corresponding receptors on neutrophil progenitor cells to stimulate neutrophil differentiation and maturation [ 67 ]. Increases in neutrophil production can help in cancer treatments by mediating cytotoxic effects on cancer cells, phagocytosing cancer cells, and by secreting cytokines that recruit other immune cells to the site of inflammation [ 2 , 21 ]. However, as previously mentioned, neutrophils have dual functions in cancer pathogenesis and can have a role in cancer metastasis [ 42 ].
Therefore, Filgrastim should be used in combination with other anticancer immunotherapies [ 67 ]. However, due to this also functioning as a macrophage colony stimulating factor, it helps increase myeloid cells any leukocyte that is not B or T cells in leukemic patients, as well as in individuals with bone marrow transplant [ 67 ].
The use of small molecules in cancer treatment as immunotherapies has also been increasing [ 1 ]. Plerixafor is a small molecule antagonist that inhibits the binding interaction of stromal cell-derived factor-1 SDF-1 to the chemokine receptor, CXCR4 [ 1 , 68 ]. This can prevent cancer metastasis and improve mobilization of hematopoietic stem cells in cancer patients, particularly pancreatic ductal adenocarcinoma patents [ 1 ]. Interaction of SDF-1 with CXCR4 mediates functions such as attracting lymphocytes in certain conditions and having critical functions for homing of hematopoietic stem cells to the bone marrow [ 69 ].
For treatment of basal cell carcinoma, Imiquimod, a small molecule agonist for TLR7 on dendritic cells and macrophages, is being used Figure 3 [ 1 ]. Imiquimod-mediated TLR7 activation induces secretion of proinflammatory cytokines, suppresses Tregs, and induces Th1 cell-mediated activation of NK cells to eradicate cancer cells [ 1 ].
This innovative form of cancer immunotherapy is known as adoptive T cell transfer. The alteration via retroviral gene transfer of autologous T cells prior to being transferred back into the patient comes from the concept of chimeric antigen receptors CARs on T cells CAR-T cells [ 70 ]. CAR-T cells are comprised of variable regions for identifying various antigens and have various downstream intracellular T cell signaling components [ 54 ]. Chemotherapy utilizes agents that are cytotoxic to rapidly proliferating cancer cells but depending on the regimen used can also be toxic to hematopoietic cells in the bone marrow [ 71 ], whereas radiation therapy exploits ionizing radiation to target cancer cell death by damaging their DNA.
However, this also damages the adjacent normal healthy cells [ 71 ]. While this section has focused on different forms of cancer immunotherapies as an individual therapy, the reality is that these cancer immunotherapies may work more effectively when used in combination [ 39 ]. The active role of the immune system in oncogenesis has been appreciated for over a century [ 4 ]. However, due to cancer heterogeneity and the distinct immune responses that can be activated, the field of immune-oncology is constantly evolving.
In the past few decades, several scientific advancements have been made that increase our understanding of various immune mechanisms that contribute to cancer pathogenesis. In addition, the identification of immune biomarkers could potentially be exploited for cancer immunotherapies [ 5 ]. While several forms of immunotherapies have been approved by the FDA or have entered the early phases of the clinical trials, there are other forms of immunotherapies that still merely remain a concept.
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Research involving the immunooncology paradigm has directed its efforts towards translating some of these conceptual immunotherapies into treatments for patients. All three of these receptors are repressive to T cells functions; therefore, development of antibodies that target and block immunosuppressive receptors on T cells will lead to optimal T cell activation and immune responses against cancer [ 54 ].
Notably, interest in small molecule inhibitors to pharmacologically intervene and block immunosuppression is emerging as another driving force in cancer immunotherapies [ 1 ]. Currently, phase II clinical trials are being performed using a small inhibitor against IDO for metastatic melanoma [ 1 ]. It mediates the conversion of tryptophan to kynurenine [ 1 ] and plays a role in immunosuppression during cancer pathogenesis [ 1 ], by inducing differentiation of Tregs [ 1 ]. Thus, by inhibiting IDO, Tregs are not induced, resulting in activation of immune responses [ 1 ].
Small molecule inhibitors targeting chemokine receptors or adenosine pathways are also being investigated for cancer immunotherapies due to their ability to recruit or activate tissue-associated macrophages TAMs , respectively [ 1 ]. These TAMs can promote cancer or tumor progression via angiogenesis and neovasculature formation [ 1 ].
Despite the progresses made in this field, one of the biggest challenges that still remains is understanding how immunooncology and cancer immunotherapies differ between adults and children [ 19 ]. While research involving the role for the immune system in pediatric cancer has been on the rise, drug development and cancer immunotherapies for children diagnosed with cancer significantly lags behind when compared to adult cancer treatments [ 19 ].
Due to the variability associated with the type of cancer, the cancer location, and the somewhat different composition of the immune cells in adults versus children, it becomes imperative to elucidate what immune cell differences are so that the proper cancer immunotherapies are selected to target specific patients [ 19 ]. This variability in cancer pathogenesis and treatment between individuals can be attributed to factors such as genetic polymorphisms which can differentially regulate the immunoediting process involved in cancer pathogenesis, as well as differentially regulating the efficacy of various cancer immunotherapies [ 60 , 76 ].
Consequently, the next frontier in immunooncology will be focused on developing personalized cancer immunotherapies tailored to each individual patient. The authors declare that there is no conflict of interests regarding the publication of this paper. Journal of Immunology Research. Indexed in Science Citation Index Expanded.
Journal Menu. Special Issues Menu. Subscribe to Table of Contents Alerts. Table of Contents Alerts. Pankita H. Renbarger 4. Abstract Interplay among immune activation and cancer pathogenesis provides the framework for a novel subspecialty known as immunooncology. Introduction The link between the immune system and cancer has been widely appreciated for over a century and was first highlighted by Rudolph Virchow over years ago [ 1 ]. Cancer Biology Being ranked as the second major cause of death in the United States, incidence of cancer and cancer-related mortality rates have been on the rise [ 6 ].
Figure 1: Overview of the immune system: innate and adaptive immunity. The innate immune responses include cells and soluble components that are nonspecific, fast-acting, and first responders in inflammation. In contrast, adaptive immunity encompasses immune components that are more specific for targeted antigens and capable of forming immunological memory [ 25 , 27 , 38 ].
Figure 2: The cancer immunoediting process. There are three phases in the cancer immunoediting process: elimination, equilibrium, and escape [ 4 ]. Elimination phase involves effector function of the immune cells to target and eradicate cancer. In the equilibrium phase a balance is obtained between progression of cancer and cancer elimination by the immune system.
We give special attention to pre- and microinvasive cervical carcinoma when reporting our findings is due to the idea that these stages can be considered as tipping points in re-formatting of the host immune system. Scheme illustrating general relations between the key levels of immune response to cervical cancer that are addressed in the chapter. Among the listed molecular sensors, the STING protein is recognized as a signaling hub Figure 2A : it can receive and redistribute signals coming from different upstream molecular partners, although the most well studied and, perhaps, most important for mammalian cells, is the cGAS-STING signaling axis [ 13 ].
Moreover, the new data from high-throughput transcriptome analysis showed that depending on the cell type, STING can alter the expression of not only the immune response-associated genes, but also many other genes that govern crucial cellular processes proliferation, apoptosis, and stress response [ 14 , 15 , 16 ]. What reasons could underlie these contradictions? On one hand, the STING-induced production of type I IFNs and activation of inflammatory reactions are obviously indispensable for the proper functioning of antigen-presenting cells APC and for further induction of adaptive antitumor response discussed in [ 13 , 19 , 20 ].
On the other hand, the increased activity of STING leads to chronic inflammation within the locus of neoplasia which is a driving force of immunosuppression and tumorigenesis. Immunohistochemical study of HPV-infected cervical epithelium and low-grade cervical lesions indeed showed reduced expression of STING in relation to normal epithelium [ 22 ], but what changes are characteristic of high grade lesions and cervical cancer are as yet unknown.
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As mentioned before, STING-mediated signaling has been most thoroughly investigated in macrophages and dendritic cells while its role in other cell populations, specifically non-myeloid cells, is not fully understood. Surprisingly, besides activation of IFN-I response these experiments revealed T cell-specific ability of STING to modulate inhibit TCR-stimulated expansion and to induce cell death through IRF3- and pdependent pathway , which is the fundamental difference from macrophages, in which stimulation of STING never leads to activation of death-associated genes [ 14 , 15 , 16 ].
The T cell-specific effect is extremely important for the prediction of therapeutic effect of STING agonists, which are currently undergoing extensive clinical trials as adjuvants in chemo-and immunotherapy of different types of cancer; however, in the case of cervical cancer the specificity of STING expression changes has not been investigated so far. As we did not find published works reporting on the level of STING in peripheral blood lymphocytes analyzed by means of immunofluorescence techniques, we first compared different commercially available kits for intracellular protein staining.
No significant change was observed for CD4CD25 subpopulation. These results are, in a certain sense, in consistence with data reported previously by others for mouse models [ 14 ]. When analyzing CD3 T cells, the same trend could be observed while the total frequencies of T cells did not differ between patients and controls. Up-regulation of STING at early stages of cervical carcinogenesis is consistent with some previous reports by other researchers and is, overall, in line with the conception of dichotomous role of STING-pathway in tumor development [ 28 ].
Previously, we also showed up-regulation of apoptotic processes in circulating lymphocytes from early-stage cervical cancer patients [ 23 ], which was correlated with the expansion of CDpositive cells including FoxP3-expressing Treg prompting further investigation of STING in T cells during virus-related carcinogenesis. Oppositely directed changes in STING expression observed in different compartments—blood T lymphocytes and neoplastic tissue—may illustrate the putative dual role of STING in virus-related carcinogenesis, which, in turn, may represent an important point in prognosing therapeutic outcome of STING stimulation.
While administration of STING agonists may occur beneficial, for example, for patients with T cell-derived cancer or other lymphoproliferative disorders due to promotion of apoptosis in malignant T cells [ 16 ], mobilization of STING activity in solid tumors may have an opposite effect due to increased apoptosis of T effectors. Summarizing, it is worth noting that the abundance of STING in T cells may imply; on one hand, their engagement in the innate immune mechanisms as was revealed by a study of Larkin and co-authors who observed induction of intact antiviral IFN-I response in mouse T cells upon stimulation with STING agonists [ 14 ] or, on the other hand, the plausibility of noncanonical functions exerted by human STING in cells of the adaptive immune system, these issues to be further investigated in the norm and in various pathological states, including virus-induced cervical cancer.
In conclusion, it is worth mentioning that such noncanonical activity of STING, specifically, ability to switch on the apoptotic pathway has been unraveled not only in T cells, but in murine B lymphocytes normal and malignant as well [ 30 ]. Regarding other types of lymphocytes, for instance, NK cells, there is limited or no information. In addition, the systemic effect of local neoplastic lesions on deviations within these innate immune cell populations, which can become detectable even earlier than the distribution of tumor-infiltrating cell populations is changed, is becoming increasingly apparent [ 32 ].
In respect of these abnormalities, a number of fundamentally important data have been obtained for cervical cancer. Under the influence of IL-6 and chemokines, myelocytes are actively recruited into the site of neoplasia, where they can differentiate into functionally impaired dendritic cells or M2-polarized macrophages to maintain pro-inflammatory environment.
Despite they have mature phenotype, dendritic cells are not able to migrate to the lymph nodes to initiate adaptive response due to the lack of appropriate homing receptors; instead they accumulate within cervical cancer stroma and secrete pro-tumorigenic and Th2-polarizing factors.
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Cervical cancer-infiltrating M2-macrophages not only fail to produce IFNs at levels required for T cell activation and proliferation, but also express ligands for the immune checkpoint molecules, for example PD-1L, thereby promoting cytotoxic T cell exhaustion [ 6 , 32 , 33 , 34 ]. Progression of precursor lesions into cervical cancer is also accompanied by an increase in the number of infiltrating neutrophils TANs displaying suppressive phenotype.
A negative correlation found between the amount of TANs and CD8 T cells in high-grade lesions cervical intraepithelial neoplasia grade 3, CIN3 or cervical cancer samples suggests that TANs can potentially contribute to inhibition of T cell activity and thereby facilitate tumor growth [ 32 ]. At the systemic level—in the peripheral blood of cervical cancer patients—higher frequency of immature low density neutrophils has been also revealed, with elevated serum levels of granulocyte colony stimulating factor G-CSF discovered not only in cervical cancer patients, but also in women with precursor lesions CIN Furthermore, patients diagnosed with cervical cancer are characterized by a systemic increase in the frequency of the tolerogenic monocyte-derived dendritic cells MoDCs , the differentiation of which is modulated by G-CSF: MoDCs that were differentiated from monocytes taken from patients with CIN3 or cervical cancer and showing higher serum level of G-CSF were able to significantly more intensively inhibit proliferation of T cells from healthy donors and to promote Treg differentiation in the ex vivo system [ 32 ].
Altogether, these data once again prove that early neoplastic lesions can be accompanied by systemic deviations in innate immunity, which in turn can influence redistribution of innate and adaptive cell populations and their interactions with each other within the tumor locus. The entirety of systemic and local immune changes is also an important point to consider when developing antitumor therapies based on adoptive DC transfer, because it is obviously these changes that determine the absence of the desired therapeutic effect such developments aimed at overcoming the suppressive impact on DC are conducted using preclinical murine models of cervical cancer, see, for example, [ 38 , 39 ].
Unlike neutrophils and suppressor populations of myeloid cells, whose contribution to the progression of solid tumors has only recently come under intense investigation, the functions of natural killer cells have always been considered in the context of cancer immunosurveillance.
However, in spite of the fact that for this group of innate lymphoid cells, a detailed spectrum of receptors allowing for recognition of transformed cells has been described and a vast diversity of mechanisms for their cytotoxic action has been established, attempts to use them in anticancer therapy occurred to be unsuccessful—the reasons for this situation are reviewed in [ 41 ], and among these reasons are the underappreciated regulatory properties of NK cells implementing via production of a wide range of cytokines, the specificity of which is largely determined by the surrounding molecular context.
Another promising concept seems to be the use of Cord-Blood NK cells that can retain a highly activated phenotype and whose expansion capacity substantially exceeds that of peripheral blood NK cells successful implementation of this approach in the preclinical model system using cervical cancer cell lines has been recently reported in [ 42 ]. Whether these negative processes have any influence on circulating NK cells during the development of cervical cancer remains a poorly studied question.
Despite the high phenotypic heterogeneity of NK cells, they can be divided into two subsets depending on the level of expression of CD56 marker: CD56bright and CD56dim. These two populations differ not only phenotypically and functionally—they are differently represented in the systemic circulation and tissues [ 45 ]. Unlike CD56dim, CD56bright NK cells represent the minor population in peripheral blood, while in the secondary lymphoid organs and other tissues CD56bright cells account for the majority of peripheral NKs.
Presently, increasing attention is being paid to CD56bright NK cells as new facts are emerging suggesting that there is no strict functional dichotomy between the so called regulatory CD56bright and cytolytic CD56dim subsets, and that CD56bright cells are capable of acquiring cytotoxicity upon appropriate stimulation with specific combinations of cytokines [ 45 ]. Immune surveillance of tumors. J Clin Invest. Immune cell promotion of metastasis.
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