|Year : 2017 | Volume
| Issue : 1 | Page : 7-15
A review on tumor immunology
Sri Lalitha Kaja, S. V. N. Sasi Kiran, Kiran Kumar Kattapagari, Ravi Teja Chitturi, S Deepika Chowdary, Baddam Venkata Ramana Reddy
Department of Oral Pathology and Microbiology, SIBAR Institute of Dental Sciences, Takkellapadu, Guntur, Andhra Pradesh, India
|Date of Web Publication||14-Jun-2017|
Sri Lalitha Kaja
Department of Oral Pathology and Microbiology, SIBAR Institute of Dental Sciences, Takkellapadu, Guntur - 522 509, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
The ability of immune system to detect and destroy the altered/abnormal cells may inhibit the development of various cancers. The immune system had been proposed as a tactic in sustaining nonneoplastic state and also for the development of immunotherapy against cancer. Although the immune system exerts a protective role, under certain circumstances, it could be damaging in terms of modulating the oncogenic process. The failure of host's immunological responses against tumor growth and dissemination implicated that both immunologic and nonimmunologic factors may work together to affect tumorigenesis. Hence, understanding the aspects pertaining to tumor immunology which deals with the complex interactions between the host's immune system and neoplasm is essential. The current review focuses on the aspects concerned with tumor immunology, steps involved, and cancer immunotherapy as a probable therapeutic tool.
Keywords: Cancer, immune escape, immunosurveillance, immunoediting, immunology, tumor
|How to cite this article:|
Kaja SL, Kiran SS, Kattapagari KK, Chitturi RT, Chowdary S D, Reddy BV. A review on tumor immunology. J Orofac Sci 2017;9:7-15
|How to cite this URL:|
Kaja SL, Kiran SS, Kattapagari KK, Chitturi RT, Chowdary S D, Reddy BV. A review on tumor immunology. J Orofac Sci [serial online] 2017 [cited 2018 Feb 21];9:7-15. Available from: http://www.jofs.in/text.asp?2017/9/1/7/207949
| Introduction|| |
Tumor immunology is the “study of the complex interaction between a human host and a neoplasm, which unless adequately treated causes the death of the host.” Frequent failure of the immunologic responses of the host to restrict tumor growth and dissemination led to the realization that both immunologic and nonimmunologic factors may act in concert to affect tumorigenesis. Numerous studies have focused on the immune system as a tactic in sustaining nonneoplastic state and also for the possibility of developing cancer immunotherapy. Although under some circumstances, immune system exerts a protective role; under other conditions, it could be damaging or irrelevant in terms of modulating the oncogenic process.
Paul Ehrlich was the first one to propose that “the immune system could repress a potentially overwhelming frequency of carcinomas” which was found to be a key for the cancer immunosurveillance hypothesis. Despite tumor immunosurveillance, development of tumors can occur even in the presence of functioning immune system, and hence an updated concept of tumor immunoediting was proposed which gives a more complex explanation for the role of immune system in tumor development. Tumors progress even in immunologically competent hosts, as they manage to escape from the immune system. The escape process is attributed to the inability of immune cells to develop an effective antitumor response or to the inhibition of functions of the immune system by tumor-derived factors.
The current review focuses on the aspects concerned with tumor immunology.
Tumor immunology includes:
- Immune evasion.
| Cancer Immunosurveillance|| |
The three primary roles of the immune system in the prevention of tumors are as follows:
- First, the immune system by eliminating or suppressing viral infections, protects the host from tumors induced by viruses
- Second, by the elimination of pathogens and prompt resolution of inflammation, it prevents the establishment of an inflammatory environment that is conducive to tumorigenesis
- Third, the immune system could specifically identify and eliminate tumor cells by the expression of tumor-specific antigens or molecules that are induced by cellular stress.
The third process by which the immune system identifies cancer or precancer cells and eliminates them before they can harm is known as “tumor immunosurveillance.”
In the 1950s, Medawar et al. implicated that cellular components of the immune system have a critical role in allograft rejection. He demonstrated that immunized mice against synergistic tumor transplants induced by viruses, chemical carcinogens, or other means established the presence of “tumor-specific antigens.” This supports the cancer immunosurveillance hypothesis.
These emerging discoveries led to the formal hypothesis of cancer immunosurveillance by Sir Macfarlane Burnet and Lewis Thomas in 1957. He stated that “it is by no means inconceivable that small accumulations of tumor cells may develop and because of their possession of new antigenic potentialities provokes an effective immunological reaction with regression of the tumor and no clinical hint of its existence.”
Thomas suggested that primary function of cellular immunity was not to promote allograft rejection but indeed to protect against neoplastic disease and maintenance of tissue homeostasis. After these speculations, Burnet in 1970 redefined the immunosurveillance concept as “In large, long-lived animals, like most of the warm-blooded vertebrates, inheritable genetic changes must be common in somatic cells and a proportion of these changes will represent a step towards malignancy. It is an evolutionary necessity that there should be some mechanism for eliminating or inactivating such potentially dangerous mutant cells and it is postulated that this mechanism is of immunological character.“Burnet and Thomas postulated that lymphocytes acted as sentinels in recognition and elimination of continuously arising transformed cells.,
The immunosurveillance theory of Burnet was based on the capability of the immune system in distinguishing between self and nonself. Tumors induced by virally encoded proteins are foreign. They are potentially immunogenic targets for the immune system that can readily identify them as “nonself.” However, whether the cancer cells of nonviral origin are recognized as self or nonself by the immune system was questionable. It was thought that transformation into a cancer cell would change from self to nonself that is recognizable by the immune system.
The concept of immunosurveillance had a dominating position in the past, but currently, it is restricted only to the virus-induced tumors. The immune system can protect the host against outgrowth of cells transformed by human papillomaviruses, Epstein–Barr virus, and human herpesvirus-8 carrying Kaposi sarcoma cells. However, they may grow into full-fledged tumors in congenitally or iatrogenically immunodefective individuals or in HIV-infected persons with immunodeficiency.
Cancer immunosurveillance represents only one dimension of the complex interaction between the immune system and cancer. Immunosurveillance could often fail due to the following factors:
- Inherited selective defects of the immune response that are mediated directly by the genes or through various mechanisms resulting in low threshold tolerance
- Absence of tumor-associated antigens (TAA)
- Shielding of TAA.
| Cancer Immunoediting|| |
Despite tumor immunosurveillance, tumors develop in the presence of functioning immune system, and hence an updated concept of tumor immunoediting was proposed which gives a more complex explanation for the role of immune system in tumor development. Recent works suggest that immune system might promote the emergence of primary tumors by reducing immunogenicity that are capable of escaping immune recognition and destruction. Cancer immunoediting describes both the host protecting and tumor sculpting actions of the immune system that not only prevents but also shapes the neoplastic disease. Cancer immunoediting can promote:
- Complete elimination of some tumors
- Generates a nonprotective immune state to some tumors
- Favors the development of immunologic anergy, tolerance, or indifference.
Evidence for cancer immunoediting in humans was supported by the number of clinical observations such as:
- Increased risk of developing tumors in immunosuppressed patients
- Instances of spontaneous tumor regression
- Presence of tumor-reactive T-lymphocytes and B-lymphocytes with respect to improved prognosis.
The ability of cancer immunoediting to control and shape cancer is the result of three phases which are called as the three E's of cancer immunoediting. The phases of cancer immunoediting are:
Elimination represents the concept of immunosurveillance. Equilibrium refers to the period of immune-mediated latency after an incomplete abolition of tumor in the elimination phase. Escape is the terminal outgrowth of tumors which have escaped the immunological restraints of the equilibrium phase.
If the tumors are successfully eradicated in this phase, it represents the complete immunoediting process without progressing to further phases. Elimination phase works out in four steps.
Initiation of antitumor responses occurs when the local tissue disruption that occurs as a result of the stromal remodeling processes at the growing tumor alerts the cells of the innate immune system. The stromal remodeling produces pro-inflammatory molecules which along with the chemokines produced by the tumor cells themselves comprise the cells of the innate system that are recruited to the site of danger. Once recruited to the tumor site, these innate cells such as the natural killer (NK) cells, γδ T-lymphocytes, and macrophages recognize molecules such as ligands for NK Group 2 D (NKG2D) ligand which have been induced on the tumor cells either by inflammation or by the cellular transformation process itself. γδ T-lymphocytes and NK cells may recognize developing tumors through T-cell receptor interaction with either NKG2D ligands or glycolipid-CD1 complexes expressed on the tumor cells, respectively. This precise mechanism of recognition leads to the progression of antitumor immune response, i.e., production of interferon-γ (IFN-γ).
In the second step, the effects of innate immune recognition of tumor are amplified. IFN-γ, released at tumor site, induces the production of chemokines such as CXCL-9, 10, and 11 from the tumor cells as well as from surrounding normal host tissue which further recruits more cells of the innate immune system to the tumor. Tumor-infiltrating macrophages are induced to produce low levels of interleukin-12 (IL-12) by the products that are generated during the remodeling of extracellular matrix. IL-12 stimulates NK cells to produce low amounts of IFN-γ, which further activates macrophages to produce more amounts of IL-12 thereby leading to increased production of IFN-γ by the NK cells. These work in a positive feedback mechanism. NK cells also produce more IFN-γ production upon stimulation by binding of NK cell receptors to their cognate ligands on tumor cells, i.e., NKG2D ligands. IFN-γ can now activate a number of IFN-γ dependent processes which enhance the killing of a proportion of the tumor. The processes activated are antiproliferative, proapoptotic, and angiostatic. IFN-γ activates macrophages that express reactive oxygen and nitrogen metabolites which are tumoricidal products. NK cells activated by IFN-γ or by engagement of their receptors can kill tumor cells either by tumor necrosis factor alpha-inducing ligand or perforin-dependent mechanisms, respectively.
The processes in the second step provide a source of tumor antigens from dead tumor cells and thereby activating tumor-specific adaptive immune responses in the third step. Dendritic cells (DC) recruited to the tumor site get activated by exposure to the cytokines generated by innate immune responses or by interacting with the tumor-infiltrating NK cells. The activated DC can acquire tumor antigens by either direct or indirect mechanisms. Direct mechanism is by the ingestion of tumor cell debris. Indirect mechanisms involve transferring of tumor cell-derived heat shock protein or tumor antigen complexes to DC. These activated antigen-bearing mature DCs migrate to the draining lymph nodes and induce the activation of naïve tumor-specific Th1 CD4+ T-cells. Th1 cells through cross-presentation of antigenic tumor peptides on DC major histocompatibility (MHC) Class I molecules facilitate the development of tumor-specific CD8+ cytotoxic T-cells.
In the fourth step, the host is provided with a capacity to completely eliminate the tumor development by means of tumor-specific adaptive immune responses. Tumor-specific CD4+ and CD8+ T-cells are primed to the site of tumor where they participate in the killing of antigen-positive tumor cells. IL-2 produced by the CD4+ T-cells together with IL-15 produced by the host cells helps to maintain the function and viability of tumor-specific cytotoxic CD8+ T-cells. CD8+ T-cells induce tumor cell death directly and also indirectly by producing IFN-γ which in turn activates IFN-γ-dependent mechanisms.
The elimination phase of cancer immunoediting is a continuous process and must be repeated each time antigenically distinct neoplastic cells arise. Hence, cancer is more prevalent in aged individuals where the functioning of immune system declines.
The host immune system and the tumor cell variant that have survived the elimination phase enter into equilibrium. Here, the lymphocytes and IFN-γ exert potent selection pressure on tumor cells which could try to extinguish a tumor bed containing many genetically unstable and mutating cells. Equilibrium phase of cancer immunoediting is the longest of all the three phases and occurs over a period of many years in humans. This is said to have the Darwinian selection; where many of the original tumor cell escape variants are destroyed, but new variants arise carrying different mutations. Different mutations in the new variants provide increased resistance to attack by the immune system. Thereby, the end result of equilibrium phase is a new population of tumor clones with reduced immunogenicity.,
Clinical evidence supporting the equilibrium phase of cancer immunoediting is provided by a number of findings.
- The existence of an immune response to premalignant monoclonal gammopathy of undetermined significant cells that eventually progress to multiple myeloma, in which the immune system is controlling, but not eliminating the premalignant cells that eventually evolve and progress to malignancy
- Passive immunization with a specific antibody and in conjunction with cytokine therapy or chemotherapy is known to induce remission in few patients having low-grade B-cell lymphoma. However, the tumor cells are not completely eliminated, and they can be detected in the blood/bone marrow for up to 8 years following clinical remission
- Pediatric acute myeloid leukemia patients on chemotherapy or chemotherapy combined with autologous bone marrow transplantation suggested a role for the immune system in establishing long-term remission
- Tumor transmission from an organ donor to recipient has also provided evidence for the equilibrium phase of cancer immunoediting. It was shown that the tumor was being held under control by an immunologic mechanism in the donor and the transplantation of organ into an immunosuppressed host allowed tumor outgrowth.
The escape phase represents the failure of the immune system to eliminate or control transformed cells, which further allows tumor cell variants to grow in an immunologically unrestricted manner. Genetic and epigenetic changes in the tumor cell confer resistance to immune detection and/or elimination, allowing the expansion of tumors and they being clinically detectable. To achieve progressive growth, the tumor cells have to circumvent either one or both the arms of the immune system, i.e., innate and adaptive immune responses in the cancer immunosurveillance network. To circumvent these responses, several distinct immunologically driven tumor sculpting events should occur before the immunogenic phenotype of a malignant cell is ultimately established.
Tumors can impede the development of antitumor immune responses either directly or indirectly which target the immune system to achieve tumor escape. It could be by:
- Expression of immunosuppressive cytokines such as transforming growth factor-β and IL-10 or
- Mechanisms involving T-lymphocytes with immunosuppressive activities, i.e., T-regulatory (TRegs) cells.
Tumor escape could also result from the changes that occur directly at the level of tumor. These include:
- Alterations that affect the recognition of tumor by immune effector cells such as loss of antigen expression, loss of MHC components, shedding of NKG2D ligands, and further development of IFN-γ insensitivity
- Tumor mechanisms to escape immune destruction such as defects in death receptor signaling pathways or antiapoptotic signal expressions such as those induced by active signal transducer and activation of transcription 3.
Of this dysregulation of MHC Class I processing and presentation and development of IFN-γ insensitivity in tumor cells, allows tumors to escape from the events in the elimination phase of the cancer immunoediting process. The unresponsive state in these tumors may be caused due to the absence/abnormal function of components in the IFN-γ receptor signaling. Tumor escape strategies finally result in a clinically detectable malignant disease, when if left unchecked results in the death of the host.
| Cancer Immune Evasion|| |
Immune evasion is a mechanism used by pathogenic organisms and tumors to evade host's immune response and to maximize their capability of transmission to a fresh host or to continue in growth, respectively. Although tumors possess tumor rejection antigens, they are capable of escaping destruction by host immunity which indicates that some form of immune evasion occurs. The escape process is attributed to the inability of immune cells to develop an effective antitumor response or to the inhibition of functions of the immune system by tumor-derived factors.
Tumors can interfere with all the components of an immune system and could also affect all the stages of immune response, but tumor-induced immunosuppression is not an immunodeficiency in a classical sense. It is selective and aggressively inhibits the functions of immune cells responsible for antitumor responses such as T-lymphocytes, B-lymphocytes, macrophages, NK cells, DC, granulocytes, and mast cells. The immune cell infiltrates may not always favor antitumor immune responses but may benefit the tumor, particularly when the tumor is aggressive. In developing an immunosuppressive environment, the tumor utilizes various strategies to:
- Regulate the cytokine/chemokine network
- Controls the regulatory cells recruitment
- Modify the expression of receptors for tumor growth-promoting factors or release of vesicular bodies that carry tumor-derived “molecular messages” in the host.
Tumors elaborate assembly of tricks to fool the immune system in general to avoid recognition.
- They either hide from immune cells thus avoiding recognition
- They proceed to disable or eliminate immune cells.
Tumors can evade the host immune response either by being (a) poor stimulators of T-lymphocytes or (b) poor targets for tumor-specific T-lymphocytes. Tumors skillfully shed their surface antigens thereby being poor stimulators for T-lymphocytes or downregulates the expression of molecules needed for interaction with immune cells and hence being poor targets for tumor-specific T-lymphocytes.
In tumor cells, the expression of molecules such as TAA, human leukocyte antigen (HLA) Class I molecules, or antigen-processing machinery components (APM) is often downregulated or altered. Abnormalities in the APM components such as downregulation, absence, or mutation do not generate peptides from TAA, or they are generated in a different form that does not allow for the formation of HLA Class I peptide complexes by the T-cells. Tumors frequently misprocessed with TAA, where the immunogenic peptides cannot be made. These immunogenic peptides cannot include in Human leukocytic antigen class I. In such cases, trimolecular HLA class I-chain-β2m-peptide is absent from the tumor cell surface. The peptide-HLA molecule complex thus formed cannot be recognized by the cytotoxic T-lymphocytes.
Another aberration in tumor cells involves the downregulated expression of costimulatory molecules on the cell surface that are essential for producing interactions with T-lymphocytes. Decreased expression of costimulatory molecules such as B7 family on tumor cells could lead to unresponsiveness based on MHC Class I restricted antigen presentation without transmission of the costimulatory signals that are critical for the activation of leukocytes.
Tumors either produce or induce factors which in turn modulate the functions of immune cells or induce apoptosis of the immune cells. These factors include a broad range of biological effector molecules such as [Table 1]:
- Several distinct receptor–ligand systems
- Small molecular species
- Cellular enzymes
- Soluble cell components
This diversity indicates that tumors are incredible in their ability to defend or debilitate the host immune responses.
Mechanisms of tumor immune escape
Mechanisms responsible for immune cell dysfunction in cancer are numerous. The escape from tumor immunity can be achieved in three principally distinct ways [Table 2]. They are by:
- Lack of recognition by means of loss or alteration of molecules which are important for the recognition and activation of the immune system
- Lack of susceptibility, i.e., escape from the effector mechanisms of cytotoxic lymphocytes
- Induction of immune dysfunction.
These mechanisms render the tumor cells less recognizable by NK cells and T-cells and also make them less susceptible to the effector molecules of the immune system. There is a continuous shaping of the tumor cell clones by both nonimmune and immunosurveillance mechanisms. This sculpting process often extends for longer periods, probably many years and perhaps for decades.
Immune escape mechanisms related to tumor metabolic changes
Tumors confront the adverse environment in two contexts. First, the developing tumors must acquire nutrients to ensure their rapid growth, and second, they must escape from the attack by host immune system. Recent studies suggest that tumor cell metabolism plays a pivotal role in tumor immune escape.
Tumor cell metabolism avoids the activities of mitochondria and oxidative phosphorylation (OXPHOS) and relies on glycolysis to produce energy which is called the Warburg effect. Warburg in 1920 found that even in the presence of ample oxygen, the tumor cells prefer to metabolize glucose by glycolysis, a metabolic pathway that converts glucose into pyruvate. Pyruvate is reduced to lactic acid by fermentation. Although it is less efficient for producing adenosine triphosphate, it is quicker than OXPHOS and confers a selective advantage to rapidly growing tumor cells. This was related to low oxygen concentration in the inner region of nascent tumors that progressively become distanced from the vasculature thereby resulting in a metabolic shift from OXPHOS to fermentation.
A new hypothesis proposes that the metabolism of tumor cells can be changed to adjust to their different needs by alterations in gene regulation, originated by deregulated expression of oncogenes. Tumor metabolic shift could be due to several processes such as overexpression of glycolytic enzymes and metabolite transporters, defective cellular respiration, and oncogenic alterations. Apart from the growth advantage given by the tumor metabolic shift, it also facilitates the immune escape of the tumor cells by a process of Darwinian selection of the clones that are able to perform the appropriate metabolic changes.
| Processing and Presentation of Tumor Antigens|| |
The antigenic peptides expressed by the tumor cells are presented by MHC molecules at the cell surface to T-lymphocytes. The presentation of peptides at the surface of tumor cells is through the classical pathways of antigen processing. Presentation of peptides to cytotoxic T-lymphocytes by MHC Class I is derived from intracellular proteins degraded by the proteasome. Peptides presented to CD4+ T-lymphocytes by MHC Class II are derived from proteins that have been transported to an endocytic compartment.
Major histocompatibility Class I presentation
Majority of peptides presented by MHC Class I molecules are produced by the proteasome and some appear to be from degradation of newly synthesized proteins, which are either misfolded or fallacious and have been called as “defective ribosomal products.” All the class I restricted tumor antigenic peptides are derived from endogenous proteins that may be either cytosolic or nuclear proteins. These peptides gain immediate access to the proteasome and return to the cytosolic proteasome through the endoplasmic reticulum-associated degradation pathway that eliminates misfolded or unassembled proteins from the endoplasmic reticulum.
Some peptides follow a different presenting pathway. For example, peptide presented by melanoma cells derived from secreted matrix metalloproteinase-2 (MMP2). The lone expression of MMP2 is not sufficient for the presentation of the peptide by Class I molecules. However, its presentation is dependent on the secretion of MMP2 in the extracellular space and subsequent uptake of exogenous MMP2 by endocytosis mediated through integrin αVβ3 that functions as a receptor of MMP2. It could be due to the blockade of the presentation of the peptide by proteasome inhibition.
Major histocompatibility Class II presentation
Tumors expressing Class II molecules present peptides to CD4+ T-lymphocytes. These peptides are derived from proteins present either at the cell surface or in intracellular organelles. Some peptides presented by the MHC Class II molecules are tyrosinase derived from the endosomes in melanosomes and melanoma-associated antigen-3. However, the pathway by which these peptides reach the Class II molecules is unclear. Recent data suggest that autophagy could be involved in the presentation of tumor antigens to MHC Class II molecule. It was revealed that large portion of MHC Class II bound peptides is derived from intracellular proteins, and this proportion appears to be correlated with autophagy.
| Cancer Immunotherapy|| |
“Immunotherapy is a treatment that uses certain parts of a person's immune system to fight diseases such as cancer.” Specific mechanisms of the immune system through antigen recognition played a key role in the possibility of immune-based therapy for cancer.
The main modes of tumor immunotherapy have been categorized as.
Stimulation of active host immune responses
- Vaccination using tumor cells and antigens:
- Immunization of tumor-bearing individuals with killed tumor cells or tumor antigens may result in enhanced immune responses against the tumor
- Augmentation of host immunity with cytokines and costimulators against tumors:
- Cell-mediated immunity to tumors may be enhanced by expressing costimulators and cytokines in tumor cells. Cytokines stimulate the proliferation and differentiation of T-lymphocytes and NK cells
- Nonspecific stimulation of immune system:
- Immune responses to tumors may be stimulated by the local administration of inflammatory substances/by systemic treatment with agents that act as polyclonal activators of lymphocytes such as anti-CD3 antibodies.
Passive immunotherapy with T-cells and antibodies
- Adoptive cellular therapy:
- It is the transfer of cultured immune cells having antitumor reactivity into a tumor-bearing host
- Therapy with antitumor antibodies:
- Tumor-specific monoclonal antibodies
- Cancer vaccines.
| Conclusion|| |
A large body of evidence implicates the potential of the immune system to control tumor promotion and the various modalities of immunotherapy that can induce strong immune responses for fighting against cancer. Such knowledge has stimulated the invention of novel immunotherapeutic modalities including therapeutic antibodies, vaccines, and cell-based treatments. Moreover, improvements in our understanding of antiapoptotic and immune escape mechanisms have resulted in the discovery of numerous biologically active drugs that can specifically target and alter such mechanisms. In the near future, the progress in cancer immunology will introduce elegant combinational treatments involving novel immunotherapeutic strategies aiming at immunostimulation with simultaneous elimination of tumor-induced suppressive mechanisms. These new therapies in cancer are expected to induce improved clinical responses and eventually cancer prevention.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Siegel BV. Tumor immunity. An overview. Am J Pathol 1978;93:515-24.
Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: From immunosurveillance to tumor escape. Nat Immunol 2002;3:991-8.
Finn OJ. Human tumor antigens, immunosurveillance, and cancer vaccines. Immunol Res 2006;36:73-82.
Swann JB, Smyth MJ. Immune surveillance of tumors. J Clin Invest 2007;117:1137-46.
Burnet FM. Cancer; a biological approach. I. The processes of control. Br Med J 1957;1:841-7.
Thomas L. On immunosurveillance in human cancer. Yale J Biol Med 1982;55:329-33.
Burnet FM. The concept of immunological surveillance. Prog Exp Tumor Res 1970;13:1-27.
Burnet M. Immunological factors in the process of carcinogenesis. Br Med Bull 1964;20:154-8.
Klein G, Klein E. Surveillance against tumors – Is it mainly immunological? Immunol Lett 2005;100:29-33.
Laroye GJ. How efficient is immunological surveillance against cancer and why does it fail? Lancet 1974;1:1097-100.
Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity 2004;21:137-48.
Penn I. Tumors of the immunocompromised patient. Annu Rev Med 1988;39:63-73.
Sengupta N, MacFie TS, MacDonald TT, Pennington D, Silver AR. Cancer immunoediting and spontaneous tumor regression. Pathol Res Pract 2010;206:1-8.
Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol 2004;22:329-60.
Gerosa F, Baldani-Guerra B, Nisii C, Marchesini V, Carra G, Trinchieri G. Reciprocal activating interaction between natural killer cells and dendritic cells. J Exp Med 2002;195:327-33.
Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature 1998;396:643-9.
Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive immunity to cancer. Annu Rev Immunol 2011;29:235-71.
Khong HT, Restifo NP. Natural selection of tumor variants in the generation of tumor escape phenotypes. Nat Immunol 2002;3:999-1005.
Villalba M, Rathore MG, Lopez- Royuela N, Krzywinska E, Garaude J. From tumor cell metabolism to tumor immune escape. Int J Biochem Cell Biol 2013;45:106-13.
Mitra R, Singh S, Khar A. Antitumour immune responses. Expert Rev Mol Med 2003;5:1-19.
Whiteside TL. Tricks tumors use to escape from immune control. Oral Oncol 2009;45:e119-23.
Whiteside TL. Immune suppression in cancer: Effects on immune cells, mechanisms and future therapeutic intervention. Semin Cancer Biol 2006;16:3-15.
Meissner M, Reichert TE, Kunkel M, Gooding W, Whiteside TL, Ferrone S, et al.
Defects in the human leukocyte antigen class I antigen processing machinery in head and neck squamous cell carcinoma: Association with clinical outcome. Clin Cancer Res 2005;11:2552-60.
Hoffmann TK, Nakano K, Elder EM, Dworacki G, Finkelstein SD, Appella E, et al.
Generation of T cells specific for the wild-type sequence p53(264-272) peptide in cancer patients: Implications for immunoselection of epitope loss variants. J Immunol 2000;165:5938-44.
Wang S, Chen L. Co-signaling molecules of the B7-CD28 family in positive and negative regulation of T lymphocyte responses. Microbes Infect 2004;6:759-66.
Malmberg KJ, Ljunggren HG. Escape from immune- and nonimmune-mediated tumor surveillance. Semin Cancer Biol 2006;16:16-31.
Seliger B, Cabrera T, Garrido F, Ferrone S. HLA class I antigen abnormalities and immune escape by malignant cells. Semin Cancer Biol 2002;12:3-13.
Seliger B. Strategies of tumor immune evasion. BioDrugs 2005;19:347-54.
Khong HT, Wang QJ, Rosenberg SA. Identification of multiple antigens recognized by tumor-infiltrating lymphocytes from a single patient: Tumor escape by antigen loss and loss of MHC expression. J Immunother 2004;27:184-90.
Wu JD, Higgins LM, Steinle A, Cosman D, Haugk K, Plymate SR. Prevalent expression of the immunostimulatory MHC class I chain-related molecule is counteracted by shedding in prostate cancer. J Clin Invest 2004;114:560-8.
Doubrovina ES, Doubrovin MM, Vider E, Sisson RB, O'Reilly RJ, Dupont B, et al.
Evasion from NK cell immunity by MHC class I chain-related molecules expressing colon adenocarcinoma. J Immunol 2003;171:6891-9.
Spaggiari GM, Contini P, Dondero A, Carosio R, Puppo F, Indiveri F, et al.
Soluble HLA class I induces NK cell apoptosis upon the engagement of killer-activating HLA class I receptors through FasL-Fas interaction. Blood 2002;100:4098-107.
Poggi A, Massaro AM, Negrini S, Contini P, Zocchi MR. Tumor-induced apoptosis of human IL-2-activated NK cells: Role of natural cytotoxicity receptors. J Immunol 2005;174:2653-60.
Restifo NP. Not so Fas: Re-evaluating the mechanisms of immune privilege and tumor escape. Nat Med 2000;6:493-5.
Roncarolo MG, Bacchetta R, Bordignon C, Narula S, Levings MK. Type 1 T regulatory cells. Immunol Rev 2001;182:68-79.
Campos L, Rouault JP, Sabido O, Oriol P, Roubi N, Vasselon C, et al.
High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood 1993;81:3091-6.
Strand S, Vollmer P, van den Abeelen L, Gottfried D, Alla V, Heid H, et al.
Cleavage of CD95 by matrix metalloproteinase-7 induces apoptosis resistance in tumour cells. Oncogene 2004;23:3732-6.
Hallermalm K, De Geer A, Kiessling R, Levitsky V, Levitskaya J. Autocrine secretion of Fas ligand shields tumor cells from Fas-mediated killing by cytotoxic lymphocytes. Cancer Res 2004;64:6775-82.
Malmberg KJ. Effective immunotherapy against cancer: A question of overcoming immune suppression and immune escape. Cancer Immunol Immunother 2004;53:879-92.
Kiessling R, Wasserman K, Horiguchi S, Kono K, Sjöberg J, Pisa P, et al.
Tumor-induced immune dysfunction. Cancer Immunol Immunother 1999;48:353-62.
Warburg O. On respiratory impairment in cancer cells. Science 1956;124:269-70.
Samudio I, Fiegl M, Andreeff M. Mitochondrial uncoupling and the Warburg effect: Molecular basis for the reprogramming of cancer cell metabolism. Cancer Res 2009;69:2163-6.
Smolková K, Plecitá-Hlavatá L, Bellance N, Benard G, Rossignol R, Ježek P. Waves of gene regulation suppress and then restore oxidative phosphorylation in cancer cells. Int J Biochem Cell Biol 2011;43:950-68.
van der Bruggen P, Van den Eynde BJ. Processing and presentation of tumor antigens and vaccination strategies. Curr Opin Immunol 2006;18:98-104.
Godefroy E, Moreau-Aubry A, Diez E, Dreno B, Jotereau F, Guilloux Y. αVβ3-dependent cross-presentation of matrix metalloproteinase-2 by melanoma cells gives rise to a new tumor antigen. J Exp Med 2005;202:61-72.
Abbas AK, Lichtman AH. Cellular and Molecular Immunology. 5th
ed. Philadelphia: Elsevier Saunders; 2005. p. 391-410.
[Table 1], [Table 2]