As research into tumor immunology continues at an incredible pace, a considerable amount of work is aimed at exploring the mechanisms that underlie the immunological recognition and elimination of cancer and the downstream consequences of these processes. The capacity of the immune system for recognition is not limited solely to the classic models of self versus pathogen or self versus non-self, but encompasses the more subtle differences that exist between self and transformed self. This conclusion provides the argument for reconsidering the largely discarded hypothesis of cancer immunosurveillance. The immune system attempts to constrain tumor growth, but sometimes tumor cells might escape or attenuate this immune pressure, similar to the way in which these cells evade classic mechanisms of tumor suppression. The dual opposing functions of immunity host protection and tumor promotion formed the conceptual basis for a process that was named cancer immunoediting. The cancer immunoediting hypothesis emphasizes that extrinsic immune pressure either can block tumor growth, development, and survival or can facilitate tumor outgrowth by sculpting tumor immunogenicity or by inhibiting host-protective anti-tumor responses. In this manner, the acquired capacity of developing tumors to escape immune control is a seventh hallmark of cancer. It is envisaged that the cancer immunoediting process consists of three phases: elimination (also known as protection), equilibrium (persistence), and escape (progression) (Ref 1).

Cancers arise by an evolutionary process during which somatic cells mutate and escape the restraints that normally rein in their unwanted expansion. Suppressing the emergence of such disregulated autonomously growing cells is an evolutionary necessity of metazoans, particularly in large, long-lived organisms where cells in regenerative tissues retain the potential for neoplastic chaos throughout life. A variety of intrinsic tumor suppressor mechanisms exist to control aberrant cell division. Transformed cells escaping intrinsic control are then subjected to extrinsic tumor suppressor mechanisms. The immune system can function as an extrinsic tumor suppressor by eliminating developing tumors long before they become clinically apparent (Ref. 2).

Cancer elimination

The elimination phase represents the original concept of cancer immunosurveillance. If this phase successfully eradicates the developing tumor, it represents the complete immunoediting process without progression to the subsequent phases. The immune system manifests its effects only after transformed cells have circumvented their intrinsic tumor-suppressor mechanisms. Initiation of the anti-tumor immune response occurs when cells of the innate immune system become alerted to the presence of a growing tumor, at least in part owing to the local tissue disruption that occurs as a result of angiogenesis or tissue-invasive growth. Stromal remodeling is induced during these processes and produces pro-inflammatory molecules which, together with chemokines that may be produced by the tumor cells themselves, summon innate immune system cells to this new source of local ‘‘danger’’.

Consistent with the ‘‘danger model’’ it is possible that DCs (Dendritic Cells) act as sentinel cells for monitoring tissue stress, damage and/or transformation. Some cytokines (IL-1 (Interleukin-1), TNF-Alpha, Type IIFN, GM-CSF (Granulocyte-Macrophage Colony Stimulating Factor), and IL-15) can promote DC differentiation and activity by multiple mechanisms, including increased crosstalk between DCs and NK cells, and, later, between DCs and T-cells. NK cells, macrophages, gamma delta T-cells, and/or NKT cells immediately recruited to the ‘‘danger’’ site and recognize molecules that have been induced on tumor cells either by the incipient inflammation or the cellular transformation process itself. In addition, T-cells and NKT cells may recognize developing tumors via TCR interaction with either MHC/tumor-associated peptide complexes expressed on tumor cells, respectively. These immune cells then employ cytotoxic effector mechanisms to eliminate the transformed cells and secrete IFNs (Interferons) that control tumor growth and amplify the immune response by a variety of mechanisms. The initial IFN-gamma released at the tumor site could then induce the local production of chemokines that recruit more cells of the innate immune system to the tumor. Products generated during remodeling of the extracellular matrix may induce a feedback loop between tumor-infiltrating macrophages. Additionally, a number of IFN-gamma-dependent processes including anti-proliferative, pro-apoptotic, and angiostatic effects may also occur that result in the killing of a proportion of the tumor. Macrophages, activated by IFN-gamma that express tumoricidal products such as reactive oxygen and reactive nitrogen intermediates and NK cells activated either by IFN-gamma or via engagement of their activating receptors, may kill tumor cells via TRAIL-dependent or Perforin-dependent mechanisms, respectively
(Ref. 2 , 3 & 4).

Cancer equilibrium

Although the elimination phase of the cancer immunoediting process can eradicate a significant percentage of transformed cells, there can exist a period of latency extending from the end of the elimination phase to the beginning of the escape phase and the emergence of clinically detectable malignant disease. This potentially protracted period in the course of the immune system/tumor interaction that occurs prior to the detection of clinically apparent tumors constitutes the equilibrium phase. Equilibrium is probably the longest of the three phases and may occur over a period of many years in humans. The events that occur in the equilibrium phase of cancer immunoediting are likely quite similar to those previously envisaged to occur in a process termed tumor ‘‘dormancy’’. Although many of the original tumor cells are destroyed, new variants arise carrying more mutations that provide them with increased resistance to immune attack. Ultimately, the dynamic interaction between immunity and cancer in the equilibrium phase produces new populations of tumor cells that are better suited for survival in the immunocompetent host. During this period, the heterogeneity and genetic instability of cancer cells that survive the elimination phase are possibly the principal forces that enable tumor cells to eventually resist host immunity (Ref. 2, 3 & 5).

Cancer escape

In the escape phase, some of the tumor cell variants that emerge from the equilibrium phase develop the capacity to grow in an immunologically-intact environment. Because both the adaptive and innate compartments of the immune system function in the cancer immunosurveillance network, tumors most likely would have to circumvent either one or both arms of immunity in order to achieve progressive growth. Tumor escape mechanisms fall into two basic categories: (1) tumor intrinsic mechanisms associated with tumor cells and tumor-associated antigens and (2) tumor extrinsic mechanisms associated with the host immune system. The former group includes: (a) Lack of expression of MHC class II molecules and co-stimulatory molecules; (b) down-regulation or loss of expression of MHC class I molecule proteins; (c) down-regulation or expression of genes associated with antigen presentation (such as TAP (Transporter Associated With Antigen Processing), LMP (Low-Molecular-Weight Protein) and beta-microglobulin); (d) low level of expression of tumor-associated antigens at early phases of tumor growth; (e) loss of antigenic epitopes; (f) physical barrier preventing effector cells accessing tumors; and (g) loss of response to IFNs . Mechanisms associated with the host immune system include: (a) ignorance; (b) tolerance of T-cells to tumor-specific antigens resulting from anergy or deletion caused by host APC, myeloid cells, or regulatory T-cells; (c) suppression of T-cells caused by tumor-derived factors [TGF-beta, IL-10, VEGF, FasL, galectin, IDO (Indoleamine 2,3-Dioxygenase)], immunosuppressive myeloid or regulatory T-cells; (d) secretion of soluble ligands that block lymphocyte activation (e.g., NKG2D-L); (e) defects in antigen presentation by professional APC; and (f) impaired APC maturation (Ref.3 , 4 & 5).

Although numerous studies using several different tumor models have revealed a definitive role for certain immune components in protecting the host from cancer, a seeming ‘controversy’ persists about whether the immune system protects against or promotes cancer. Perhaps this conflict arises from the inaccurate generalization of immune function. To state simply that ‘‘the immune system protects against cancer’’ is just as accurate (or as inaccurate) as to state ‘‘the immune system promotes cancer’’. Clearly, not all immune components play fixed roles in all models of cancer. Hence the relationship between cancer immunoediting and cancer promoting inflammation cannot be simply defined based on single tumor models, and in fact might change even within related systems. Thus, it is suggested that rather than developing models to segregate immunosurveillance from inflammation-induced cancer, tumor immunologists should attempt to understand the factors that help orchestrate which immune cells are cast in a protagonist versus antagonist role. The tumor microenvironment represents a complex system in which individual immune cells make potentially interconnected decisions to attack tumor cells, ignore their presence, or enhance their development and/or survival. These decision-making processes, and the potential to beneficially influence them in the clinical setting, represent significant areas of research that beckon future studies (Ref. 6 & 7).


Cancer Immunoediting


Pathway Key

  1. Interferons, immunity and cancer immunoediting. Dunn GP, Koebel CM, Schreiber RD. Nat Rev Immunol. 2006 Nov;6(11):836-48.
  2. Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Smyth MJ, Dunn GP, Schreiber RD. Adv Immunol. 2006;90:1-50.
  3. The three Es of cancer immunoediting. Dunn GP, Old LJ, Schreiber RD Annu Rev Immunol. 2004;22:329-60.
  4. Cancer immunoediting: from immunosurveillance to tumor escape. Dunn GP, Bruce AT, Ikeda H,Old LJ, Nat Immunol. 2002 Nov;3(11):991-8.
  5. The immunobiology of cancer immunosurveillance and immunoediting. Dunn GP, Old LJ, Schreiber RD. Immunity. 2004 Aug;21(2):137-48.
  6. Cancer immunosurveillance, immunoediting and inflammation: independent or interdependent processes? Bui JD, Schreiber RD. Curr Opin Immunol. 2007 Apr;19(2):203-8. Epub 2007 Feb 9.
  7. Cancer despite immunosurveillance: immunoselection and immunosubversion. Zitvogel L, Tesniere A, Kroemer G. Nat Rev Immunol. 2006 Oct;6(10):715-27. Epub 2006 Sep 15.