R EVIEW
Cancer immunoediting: from immuno-
surveillance to tumor escape
Gavin P. Dunn1, Allen T. Bruce1, Hiroaki Ikeda1, Lloyd J. Old2 and Robert D. Schreiber1
© 2002 Nature Publishing Group http://www.nature.com/natureimmunology
The concept that the immune system can rec-
ognize and destroy nascent transformed cells
was originally embodied in the cancer immuno-
surveillance hypothesis of Burnet and Thomas.
This hypothesis was abandoned shortly after-
wards because of the absence of strong experi-
mental evidence supporting the concept. New
data, however, clearly show the existence of can-
cer immunosurveillance and also indicate that
it may function as a component of a more gen-
eral process of cancer immunoediting. This
process is responsible for both eliminating
tumors and sculpting the immunogenic pheno-
types of tumors that eventually form in
immunocompetent hosts. In this review, we will
summarize the historical and experimental
basis of cancer immunoediting and discuss its
dual roles in promoting host protection against
cancer and facilitating tumor escape from
immune destruction.
Since the formalized introduction of the cancer immunosurveillance
concept, the idea that the immune system may have a protective role in
tumor development has been hotly debated. Recent work, however, has
lent new support to the idea’s central principle that the immune system
can indeed prevent tumor formation. At the same time, this work has
shown that the immune system also functions to promote or select
tumor variants with reduced immunogenicity, thereby providing devel-
oping tumors with a mechanism to escape immunologic detection and
elimination. These findings have led to the development of the cancer
immunoediting hypothesis, a refinement of cancer immunosurveillance
that takes a broader view of immune system–tumor interactions by
acknowledging both the host-protecting and tumor-sculpting actions of
the immune system on developing tumors. Here we discuss first the his-
tory that led to formulation of the original cancer immunosurveillance
concept and then review the data that prompted the wide-scale aban-
donment of the hypothesis. We continue with a summary of the data
underlying the development of the cancer immunoediting concept and
present a unifying model that proposes the molecular and cellular
dynamics of the process. We conclude by highlighting the critical
implications that immunoediting may have on the development and
treatment of cancer in humans.
1
Department of Pathology and Immunology, Center for Immunology,Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA. 2Ludwig
Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. Correspondence should be addressed to R. D. S.
(schreiber@immunology.wustl.edu).
www.nature.com/natureimmunology • november 2002
The cancer immunosurveillance hypothesis
Paul Ehrlich was one of the first to conceive the idea that the immune
system could repress a potentially “overwhelming frequency” of car-
cinomas1. The idea of immune control of neoplastic disease was not
vigorously pursued, however, until the midpoint of the twentieth cen-
tury. To a large extent, the revisiting of the Ehrlich proposal had to
await the maturation of the developing field of immunology. In the
1950s, the work of Medawar and colleagues clarified the critical role
for cellular components of immunity in mediating allograft rejection2.
This work cast doubt on data that were used to argue for the existence
of tumor antigens. Specifically, although it was generally accepted that
the immune response was capable of recognizing and destroying trans-
planted tumors derived from noninbred strains of mice, it soon became
clear that the underlying mechanism was one of allograft rejection
rather than tumor-specific rejection. With the availability of inbred
strains of mice, the idea that tumors were immunologically distin-
guishable from normal cells could be critically tested. The demonstra-
tion that mice could be immunized against syngeneic transplants of
tumors induced by chemical carcinogens, viruses or other means
established the existence of “tumor-specific antigens”3,4 and provided
a key cornerstone of the cancer immunosurveillance hypothesis.
Clearly, there could be no tumor immunosurveillance if there were no
distinctive structures on tumor cells that could be recognized by the
immune system.
These emerging discoveries were incorporated into the formal
hypothesis of “cancer immunosurveillance” proposed by Sir
Macfarlane Burnet and Lewis Thomas. In 1957, Burnet stated5:
It is by no means inconceivable that small accumulations of tumour
cells may develop and because of their possession of new antigenic
potentialities provoke an effective immunological reaction with regres-
sion of the tumour and no clinical hint of its existence.
At about the same time, Thomas suggested that the primary function
of cellular immunity was in fact not to promote allograft rejection but
rather to protect from neoplastic disease, thereby maintaining tissue
homeostasis in complex multicellular organisms6. These speculations
formed the evolutionary framework that ultimately resulted in the devel-
opment of the immunosurveillance concept, which was defined by
Burnet as follows7,8:
In large, long-lived animals, like most of the warm-blooded vertebrates,
inheritable genetic changes must be common in somatic cells and a pro-
portion of these changes will represent a step toward 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.
• volume 3 no 11 • nature immunology 991
 R EVIEW
Both Burnet and Thomas speculated that lymphocytes acted as sen-
tinels in recognizing and eliminating continuously arising, nascent
transformed cells7.
Challenging the immunosurveillance hypothesis
The introduction of the immunosurveillance hypothesis was rapidly
followed by many experiments aimed at testing its logical predic-
© 2002 Nature Publishing Group http://www.nature.com/natureimmunology
tions—namely, that hosts with impaired immune systems would exhib-
it increased incidences of spontaneous or chemically induced tumors.
The earliest approaches explored whether tumor development in mice
was influenced by experimental immunosuppression of the host9,10.
Whereas several groups used neonatal thymectomy to induce immuno-
suppression in mice, they could not reach a consensus as to the effects
of this treatment on the incidence of either chemically induced10–13 or
spontaneous tumors10,14,15. Other groups who compromised the immune
system of mice using either heterologous anti-lymphocyte serum or
pharmacologic methods obtained similar discordant results10. It also
became clear that mice with induced immunodeficiencies showed a
high susceptibility to virally induced tumors and a greater tendency to
develop spontaneous lymphomas compared with immunocompetent
mice. The prevailing view about these observations, however, was that
they reflected the greater susceptibility of immunocompromised hosts
to infectious agents, such as transforming viruses. The greater frequen-
cy of lymphomas could also be ascribed to chronic antigenic stimula-
tion from defective control of bacterial or viral infections, resulting in
increased lymphocyte proliferation, somatic mutation and eventually
the formation of lymphomas10,16. As a group, these studies were incon-
clusive and therefore failed either to prove or disprove the immunosur-
veillance hypothesis.
The identification and characterization of the athymic nude
mouse17,18 enabled researchers to study tumor formation in a host with
a genetic immunologic impairment. The work of Osias Stutman repre-
sents one of the most extensive uses of nude mice to explore whether
immunosurveillance occurs in a physiologic setting. Stutman found
that CBA/H strain nude mice did not form more chemically induced
tumors compared with their wild-type counterparts, nor did they show
a shortened tumor latency period after carcinogen injection. For exam-
ple, in one experiment, nude mice or immunocompetent mice that were
heterozygous for the nude mutation were injected subcutaneously with
0.1 mg of the chemical carcinogen methylcholanthrene (MCA) at birth
and were monitored for tumor incidence19. After 120 days, seven of 39
control mice formed tumors at the injection site with a mean time to
tumor appearance of 95 days. Of the nude mice tested, five of 27
formed tumors with a mean time to tumor appearance of 90 days. The
similarity between immunocompetent and nude mice was maintained
in subsequent experiments that employed mice of different ages, dif-
ferent doses of carcinogen and even in experiments where the observa-
tion period was extended out to 420 days20,21. At least one other group
corroborated these results22. In addition, Stutman showed that there
were no statistically significant differences in the incidence of sponta-
neous nonviral tumor formation between nude and wild-type mice23.
These findings were supported by a study of Rygaard and Povlsen that
showed no differences in spontaneous tumor formation in 10,800 nude
mice over a study period of 3–7 months24,25. The results using nude mice
were thus more conclusive than those based on experimental immuno-
suppression and failed to uphold the central predictions of the immuno-
surveillance concept. Based on the limited understanding of the
immunologic defects in the nude mouse available at that time, these
results were highly convincing and thus led to the abandonment of the
immunosurveillance hypothesis.
992 nature immunology • volume 3 no 11
In hindsight, however, there are important caveats to these experi-
ments. First, it is now clear that nude mice are not completely immuno-
compromised. Although nude mice possess fewer T cells than wild-
type mice, they have detectable populations of functional αβ T cell
receptor–bearing lymphocytes26–28. Therefore, it is not possible to pre-
dict the functional effect of these T cells on tumor formation when
compared with wild-type controls. Second, the strain of mice used in
the Stutman experiments may have been highly sensitive to MCA-
induced tumor formation. MCA requires biotransformation from its
pro-form into its carcinogenic form by the aryl hydrocarbon hydroxy-
lase enzyme system. It is now known that various inbred mouse strains
produce distinctive patterns of these enzyme isoforms with different
specific activities29. The CBA/H strain mouse used in the Stutman stud-
ies expresses a form of the enzyme with a high specific activity30, and
thus cellular transformation induced by MCA might occur in these
mice at a rate that overwhelms host immunological defense mecha-
nisms. Third, even though the study of Rygaard and Povlsen used large
numbers of nude mice, monitoring periods of 3–7 months were proba-
bly too short to see spontaneous tumor formation in the face of fully
functional intrinsic tumor suppressor systems (such as p53). Last, these
studies were carried out before the discovery of other lymphocyte pop-
ulations such as natural killer (NK) cells, which are not thymus depen-
dent, and γδ T cells, a subset of which may develop extrathymically31.
The lack of convincing support for the immunosurveillance concept
left room for other theories on the possible functions of immune cells
during the development of neoplasia. For example, Prehn proposed
that the immune system can actually promote the growth of tumors. In
this “immunostimulation theory”32, the presence of tumor rejection
antigens (TRAs) on tumors is explained by the argument that the
immune cells that recognize these TRAs provide a positive growth sig-
nal to the tumor cells. Although this theory was speculative rather than
evidence based, it reflected the mood that the proponents of the
immunosurveillance theory were overstating their case. Especially
after the Stutman experiments, enthusiasm for the original immuno-
surveillance concept began to wane. Thomas later noted, “The great-
est trouble with the idea of immunosurveillance is that it cannot be
shown to exist in experimental animals”33.
During the ensuing years, little interest was paid to the possibility that
the immune system could prevent the development of nonvirally
induced tumors. By all intents and purposes, the cancer immunosurveil-
lance concept was considered dead by 1978, and the field of tumor
immunology moved on to study other issues such as the definition and
molecular nature of mouse and human tumor antigens, the immune
response to known tumor antigens and the development of immunother-
apeutic strategies to treat cancer. This view relegated immunosurveil-
lance to the historical dust bin and was clearly echoed in a major review
that appeared in 2000, which listed the six critical hurdles that a devel-
oping tumor must circumvent to grow and survive34. No significant men-
tion was made of the natural immune response against tumors.
The renaissance of cancer immunosurveillance
Between the mid-1970s and 1990s, researchers made several experi-
mental attempts to resurrect the cancer immunosurveillance concept.
The discovery of NK cells led to a considerable amount of enthusiasm
over the possibility that they functioned as the effectors of immunosur-
veillance35. This enthusiasm was dampened, however, when a precise
definition and understanding of these cells was difficult to obtain.
Subsequently, others repeated the MCA induction experiments of
Stutman using nude mice on a BALB/c background36. When they inject-
ed nude and control mice with different doses of MCA and monitored
• november 2002 • www.nature.com/natureimmunology

them for tumor development, nude mice formed more tumors than con-
trols. These data were limited, however, in their statistical power
because of the small experimental group sizes and the magnitude of the
differences. Similar suggestive results were obtained when tumor for-
mation induced by MCA was compared between groups of wild-type
BALB/c mice and immunodeficient CB-17 severe-combined immunod-
eficiency (SCID) mice37. The latter lack a functionally active subunit of
© 2002 Nature Publishing Group http://www.nature.com/natureimmunology
the DNA-dependant protein kinase (DNA-PK) enzyme (DNA-PKcs)
that is required to generate rearranged antigen receptors in lympho-
cytes38, and thus they are unable to develop antigen-specific immune
responses. However, DNA-PKcs (and the intact DNA-PK enzyme) is
normally expressed in all cells and is important in repairing double-
stranded DNA breaks39, which includes those that can potentially be
transforming. Thus, it was not possible to interpret the basis for the
increased tumor incidence observed in SCID mice because of an inabil-
ity to differentiate between tumor suppressor roles for the immune sys-
tem or for the DNA-PK enzyme itself.
Between 1994 and 1998, two key findings incited renewed interest
in the process of cancer immunosurveillance. First, endogenously pro-
duced interferon γ (IFN-γ) was shown to protect the host against the
growth of transplanted tumors and the formation of primary chemical-
ly induced and spontaneous tumors. Using tumor transplantation
approaches, researchers found that immunogenic fibrosarcomas grow
faster and more efficiently in mice treated with neutralizing mono-
clonal antibodies specific for IFN-γ40. Overexpression of a dominant-
negative mutant of the IFN-γ receptor α subunit (IFNGR1) in sarco-
mas such as Meth A (BALB/c derived) or MCA-207 (C57BL/6
derived) completely ablated tumor sensitivity to this cytokine, and the
tumors displayed enhanced tumorigenicity and reduced immunogenic-
ity when transplanted into naïve syngeneic hosts40. Experiments based
on models of MCA-induced tumor formation showed that 129/SvEv
mice that were lacking either the IFN-γ receptor or signal transducer
and activator of transcription 1 (STAT1, the transcription factor that is
important in mediating IFN-γ receptor signaling) were found to be
approximately 10–20 times more sensitive than wild-type mice to the
tumor-inducing capacity of MCA, developed more tumors than their
wild-type counterparts and showed a shortened tumor latency period41.
Subsequent independent experiments using mice on a different genet-
ic background that lacked the gene encoding IFN-γ confirmed these
results42. Similarly, mice lacking the genes encoding the tumor sup-
pressor p53 and the IFNGR1 subunit of the IFN-γ receptor formed a
wider spectrum of tumors as compared with IFN-γ-sensitive mice
lacking only p5341. In addition, IFN-γ–/– mice on a C57BL/6 back-
ground showed an increased incidence of disseminated lymphomas
despite the presence of a normal p53 tumor suppressor gene, and IFN-
γ–/– mice on a BALB/c background showed a low incidence of lung
adenocarcinomas43.
The second key finding was the observation that C57BL/6 mice lack-
ing perforin (perforin–/–) were more prone to MCA-induced tumor for-
mation compared with their wild-type counterparts. Perforin is a com-
ponent of the cytolytic granules of cytotoxic T cells and NK cells that
is important in mediating lymphocyte-dependent killing of many dif-
ferent target cells including tumor cells44. After challenge with MCA,
perforin–/– mice developed significantly more tumors compared with
perforin-sufficient mice treated in the same manner42,45,46. Untreated
perforin–/– mice also showed a high incidence of spontaneous dissemi-
nated lymphomas, which was greater on a p53+/– background47, and a
low incidence of spontaneous lung adenocarcinomas43. Taken together,
these observations showed that components of the immune system
were involved in controlling primary tumor development.
www.nature.com/natureimmunology • november 2002
R EVIEW
The definitive work supporting the existence of a cancer immuno-
surveillance process that is dependent on both IFN-γ and lympho-
cytes came through the use of gene-targeted mice that lack recom-
bination activating gene 1 (RAG-1) or RAG-2. Like DNA-PK, these
enzymes are involved in the repair of double-stranded DNA breaks,
but unlike DNA-PK, they are expressed exclusively in the lymphoid
compartment. Mice deficient in either of these genes fail to
rearrange lymphocyte antigen receptors and thus completely lack
natural killer T (NKT), T and B cells48. In contrast, DNA repair
mechanisms in the nonlymphoid compartment of these mice are
completely normal.
For the first time, inbred strains of mice were available that carried
genetically defined mutations affecting specific tissues that led to an
absence of lymphocytes bearing antigen receptors. These mice enabled
researchers to carry out carcinogenesis experiments that could unequiv-
ocally be interpreted. After MCA injection, 129/SvEv RAG-2–/– mice
developed sarcomas more rapidly and with greater frequency than
genetically matched wild-type controls49. After 160 days, 30 of 52
RAG-2–/– mice formed tumors, compared with 11 of 57 wild-type mice.
In addition, RAG-2–/– mice aged in a specific pathogen free mouse facil-
ity formed far more spontaneous epithelial tumors than did wild-type
mice housed in the same room49 (and unpublished data). Specifically,
26 of 26 RAG-2–/– mice aged 13–24 months developed spontaneous
neoplasia, predominantly of the intestine; eight of these mice had pre-
malignant intestinal adenomas, 17 had intestinal adenocarcinomas and
one had both an intestinal adenoma and a lung adenocarcinoma. In con-
trast, only five of 20 wild-type mice aged 13–24 months developed
spontaneous neoplasia, which was predominantly benign. Three of the
wild-type mice developed adenomas of the Harderian gland, lung and
intestine, respectively, whereas the other two developed an adenocarci-
noma of the Harderian gland and an endometrial stromal carcinoma.
Thus, lymphocytes in a mouse not only protect the host against forma-
tion of primary sarcomas that are chemically induced but also prevent
the development of spontaneous epithelial tumors.
The overlap between the tumor suppressor pathways that depend on
IFN-γ and lymphocytes was defined by comparing tumor formation in
129/SvEv mice lacking IFN-γ responsiveness (IFNGR1 receptor–/– or
STAT1–/– mice), lymphocytes (RAG-2–/– mice) or both RAG-2 and
STAT1 (RkSk mice)49. Each of the four lines of gene-targeted mice
formed three times more chemically induced tumors than syngeneic
wild-type mice when injected with 0.1 mg of MCA. Because no sig-
nificant differences were detected between any of the groups of defi-
cient mice, the researchers concluded that the two extrinsic tumor sup-
pressor mechanisms heavily overlapped. RkSk mice, however, addi-
tionally developed spontaneous breast tumors that were not observed in
wild-type or RAG-2–/– mice, therefore demonstrating that the overlap
between the two tumor suppressor pathways was not complete. Similar
findings were made in carcinogenesis experiments with mice that
lacked perforin, IFN-γ or both, in which a small increase was observed
in tumor induction in the doubly deficient mice compared with mice
lacking only one of the two components42.
Additional studies have used other inbred mouse lines with targeted
disruptions in genes encoding critical components of the immune sys-
tem. They not only support the importance of immune system control of
tumor formation but also suggest the involvement of both the innate and
adaptive immune compartments in cancer immunosurveillance.
Specifically, genetic, immunochemical or functional ablations of NKT,
γδ T cells, NK cells, αβ T cells, IFN-γ or interleukin 12 (IL-12) all lead
to increased susceptibility of the host to tumors (Table 1). One of these
studies has shed light on the specific subsets of lymphocytes expressing
• volume 3 no 11 • nature immunology 993
 R EVIEW

T cell receptors (TCR) that are important in tumor surveillance. The rel-
ative contributions of αβ and γδ T cells in blocking primary tumor for-
mation were explored in αβ T cell–/– (lacking the TCR β-chain) or γδ T
cell–/– (lacking the TCR δ-chain) mice50. MCA treatment of either type
of mouse increased the incidence of fibrosarcomas and spindle cell car-
cinomas as compared with wild-type controls. These data showed that
both T cell subsets are critical for protecting the host in this particular
© 2002 Nature Publishing Group http://www.nature.com/natureimmunology
concept as originally envisaged by Burnet and Thomas—namely, that
the unmanipulated immune system is capable of recognizing and elimi-
nating primary tumors and that lymphocytes and the cytokines they pro-
duce are important in this process.
Cancer immunosurveillance in humans
If indeed cancer immunosurveillance exists in mice, does it exist in

model of tumor development. In an initiation and promotion model of humans? The logical prediction from the immunosurveillance hypoth-
skin tumorigenesis induced by 7,12-dimethylbenzanthracene (DMBA) esis is that immunodeficient or immunosuppressed humans should
and 12-O-tetradecanoylphorbol-13-acetate (TPA), however, γδ T cell–/– show greater incidences of cancer. Early follow-up studies of transplant
mice showed a greater susceptibility to tumor formation and a higher patients who were immunosuppressed51 and individuals with primary
incidence of papilloma-to-carcinoma progression than wild-type mice, immunodeficiencies52 showed that they had a significantly higher rela-
whereas αβ T cell–/– mice did not. This result suggests that immunosur- tive risk for cancer development. Based on long-term studies of
veillance may be a heterogeneous process requiring the actions of dif- patients, it is clear that some of this higher risk was due to the devel-
ferent immune effectors in a manner that is dependent on the tumor’s opment of tumors of viral origin53. For example, in the transplant reg-
cell type of origin, mechanism of transformation, anatomical localiza- istries from Cincinnatti53, Scandinavia54, and Australia and New
tion and mechanism of immunologic recognition. In sum, the large Zealand55, particularly high incidence ratios have been observed for
amount of recent data obtained by many independent groups over- non-Hodgkin’s lymphoma, Kaposi’s sarcoma and carcinomas of the
whelmingly supports the basic tenets of the cancer immunosurveillance genitourinary and anogenital regions. Many of these cancers have a
viral etiology and are linked to infection
with Epstein-Barr virus, human her-
Table 1. Enhanced susceptibility of immunodeficient mice to formation of chemically pesvirus 8 and human papilloma virus,
induced and spontaneous tumors respectively56. These malignancies are
now occurring with increasing frequency
Phenotype or depletion Immunodeficiency Tumor susceptibility in AIDS patients56. The increased inci-
dence of virally induced tumors in
RAG-2–/– T, B and NKT cells MCA-induced sarcomas49
Spontaneous intestinal neoplasia49 immunocompromised patients represents
RAG-2 × STAT1
–/– –/–
T, B and NKT cells MCA-induced sarcomas 49 one immunosurveillance function that is
(RkSk) Insensitive to IFN-γ and IFN-α/β Spontaneous intestinal and not contested: natural protection against
mammary neoplasia49 infectious organisms. These data, howev-
BALB/c SCID T, B and NKT cells MCA-induced sarcomas100 er, do not invalidate the possibility that the
Perforin–/– Lack of perforin MCA-induced sarcomas42,45,46 immune system protects humans against
Spontaneous disseminated development of tumors of nonviral origin.
lymphomas43,47 Clearly, the difficulty in assessing can-
TCR Jα281–/– Subset of NKT cells MCA-induced sarcomas42,46,100 cer immunosurveillance in immunodefi-
Anti-asialo-GM1 antibody NK cells and activated macrophages MCA-induced sarcomas100 cient humans arises from their greater sus-
Anti-NK1.1 antibody NK and NKT cells MCA-induced sarcomas 46,100 ceptibility to endemic viruses and other
Anti-Thy1 antibody T cells MCA-induced sarcomas46,100
pathogens as well as viral reactivation.
This can confound the likelihood of find-
αβ T cell–/– αβ T cells MCA-induced sarcomas50
ing spontaneous tumors of nonviral origin,
γδ T cell–/– γδ T cells MCA-induced sarcomas50
which develop slowly because of the
DMBA/TPA-induced skin tumors50
shortened life spans and other intercurrent
STAT1–/– Insensitive to IFN-γ and IFN-α/β MCA-induced sarcomas41,49
Wider tumor spectrum in
medical problems of these patients.
STAT1–/– × p53–/– (ref. 41) Greater relative risk ratios have, however,
IFNGR1 receptor –/–
Insensitive to IFN-γ MCA-induced sarcomas 41,49 been observed for a broad subset of
Wider tumor spectrum in tumors with no apparent viral etiology.
IFN-γ receptor–/– × p53–/– (ref. 41) Approximately fourfold increases in the
IFN-γ–/– Lack of IFN-γ MCA-induced sarcomas42 incidence of de novo malignant melanoma
C57BL/6: Spontaneous disseminated after organ transplantation have been
lymphomas43 reported57,58. A review of data accumulated
BALB/c: Spontaneous lung by the Cincinnati Transplant Tumor
adenocarcinoma43 Registry from 1968 to 1995 found a
Perforin–/– × IFN-γ–/– Lack of perforin and IFN-γ MCA-induced sarcomas42 twofold greater risk in transplant patients
Spontaneous disseminated
43
for developing melanoma over that of the
lymphomas
–/– 46
general population59. In addition, whereas
IL-12 Lack of IL-12 MCA-induced sarcomas
only 0.3–0.4% of melanomas occur in the
WT + IL-12 Exogenous IL-12 Lower incidence of MCA-induced general pediatric population, the occur-
101
sarcomas
rence in pediatric transplant patients was
4%59. The same database showed that
Methylcholanthrene-treated wild-type (WT) mice were treated with IL-12 during tumor formation.
transplant patients were three times more

994 nature immunology • volume 3 no 11 • november 2002 • www.nature.com/natureimmunology

 R EVIEW

likely to develop non-Kaposi’s

sarcomas60. When neoplasia
a b c
occurrence was assessed in 608
cardiac transplant patients at the
University of Pittsburgh be-
tween 1980 and 1993, the preva-
lence of lung tumors was 25-
© 2002 Nature Publishing Group http://www.nature.com/natureimmunology

fold higher than in the general

population61. In Australia and
New Zealand, the tracking of
925 patients who received
cadaveric renal transplants from
1965 to 1998 showed increased
risk ratios for development of
colon, pancreatic, lung and
endocrine tumors as well as
malignant melanomas55. In addi-
tion, assessment of 5,692 renal Figure 1. The three Es of cancer immunoediting. Cancer immunoediting encompasses three process. (a) Elimination
transplant patients from 1964 to corresponds to immunosurveillance. (b) Equilibrium represents the process by which the immune system iteratively selects
1982 in Finland, Denmark, and/or promotes the generation of tumor cell variants with increasing capacities to survive immune attack. (c) Escape is the
process wherein the immunologically sculpted tumor expands in an uncontrolled manner in the immunocompetent host. In a
Norway and Sweden showed and b, developing tumor cells (blue), tumor cell variants (red) and underlying stroma and nontransformed cells (gray) are shown;
higher standardized cancer inci- in c, additional tumor variants (orange) that have formed as a result of the equilibrium process are shown. Different lympho-
dence ratios for colon, lung, cyte populations are as marked.The small orange circles represent cytokines and the white flashes represent cytotoxic activi-
bladder, kidney, ureter and ty of lymphocytes against tumor cells.
endocrine tumors as well as
malignant melanomas as com-
pared with the general population54. Thus, individuals with severe that the immune system functions during tumor formation to select for
deficits of immunity indeed have a higher probability of developing a tumor variants that are better suited to survive in an immunologically
variety of cancers with no known viral etiology. intact environment, very much like it does with viruses, bacteria and
In addition to the supporting epidemiological data described above, parasites. Many studies have shown the immunoselective effects of
there is accumulating evidence showing a positive correlation between repassage of transplantable tumors through immunocompetent hosts
the presence of lymphocytes in a tumor and increased patient survival. and the generation of tumor variants with reduced immunogenicity.
Some of the most convincing evidence comes from the study of cuta- Two particularly informative studies used P815 mastocytomas73 and
neous melanomas. Three categories were established for tumor lym- ultraviolet-induced 1591 fibrosarcomas74. In contrast, few studies have
phocyte infiltration during the vertical growth phase of cutaneous compared the immunogenic characteristics of tumors originally gener-
melanoma (brisk, nonbrisk and absent)62. Sorting more than 500 ated in the presence or absence of a functional immune system. This
patients with primary melanoma who had 5-, 8- or 10-year follow-ups issue was difficult to study in the past because matched sets of tumors
into these categories and comparing their survival statistics showed that derived from isogenic immunodeficient and control immunocompetent
patients in the brisk tumor infiltrating lymphocyte (TIL) response cate- hosts were not generally available. A recent study, however, was carried
gory survived one and one-half to three times longer than patients in the out using many MCA-induced sarcomas obtained from either RAG-2–/–
absent TIL response group; patients in the nonbrisk response group had or wild-type mice on a pure 129/SvEv background49. When tumors iso-
intermediate survival times62,63. Researchers obtained the same prog- lated from wild-type or RAG-2–/– mice were transplanted into RAG-2–/–
nostic correlation when the presence of TILs in melanomas that had recipients, they all grew with similar kinetics, which indicates that there
metastasized to the lymph nodes was used as the criterion64. Similar were no inherent growth differences between tumors raised in the pres-
correlations between the presence of TILs and patient survival have ence or absence of an intact immune system. In addition, 17 of 17 sar-
also been made that involved more than 3,400 patients with cancer of comas originally isolated from wild-type mice were capable of estab-
the breast65, bladder66, colon67,68, prostate69, ovary70 or rectum71 and for lishing progressively growing tumors when transplanted into naïve
neuroblastoma72. In some cases, the correlation has been refined to immunocompetent 129/SvEv hosts. In contrast, 8 of 20 tumors origi-
show that CD8+ T cells are the relevant lymphocyte population that nally generated in RAG-2–/– mice were rejected when transplanted into
affect survival68. immunocompetent hosts, even when they were injected at a high cell
In sum, the data obtained from both mouse and human studies pro- number. Thus, tumors formed in the absence of an intact immune sys-
vide strong support for the existence and physiologic relevance of can- tem are, as a group, more immunogenic than tumors that arise in
cer immunosurveillance. These findings have rekindled generalized immunocompetent hosts.
interest in this process and have stimulated much work aimed at defin- Other more limited experiments have reached similar conclusions.
ing its immunologic components. Thus, the new millennium has wit- MCA-induced sarcomas derived from nude75 or SCID mice37 were
nessed the resurrection of this old and formerly controversial idea. rejected more frequently than similar tumors derived from wild-type
mice when transplanted into wild-type hosts. In addition, two MCA-
Immunologic sculpting during tumor development induced sarcomas derived from TCR Jα281–/– mice, which lack a major
Given the existence of cancer immunosurveillance, why then do can- population of NKT cells, grew more slowly when transplanted into
cers occur in immunocompetent individuals? It has long been thought wild-type hosts than did sarcomas originally isolated from wild-type

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 R EVIEW

mice46. In contrast, these tumors grew in a comparable manner when
transplanted into TCR Jα281–/– recipients. Finally, lymphomas derived
from perforin–/– mice grew avidly when transplanted into perforin–/–
mice, but most were rejected when transplanted into wild-type mice43.
Taken together, these results show that tumors are imprinted by the
immunologic environment in which they form. This imprinting process
can often result in the generation of tumors that are better able to with-
© 2002 Nature Publishing Group http://www.nature.com/natureimmunology
most tumors that are clinically apparent has already been modified to
some degree by their interactions with the immune system.
Cancer immunoediting
Because the immune system exerts both host-protecting and tumor-
sculpting effects on developing tumors, the term cancer immunosur-
veillance may no longer be appropriate to accurately describe the

stand the tumor-suppressing actions of the immune system by elimi-
nating tumor cells of intrinsically high immunogenicity but leaving
behind tumor variants of reduced immunogenicity (or that have
acquired other mechanisms to evade or suppress immune attack) that
have a better chance of surviving in the immunocompetent host. The
alterations that must occur during the immunologic sculpting of a
developing tumor are probably facilitated by the inherent genetic insta-
bility of tumors76. Some of the likely targets of the immunologic
process that sculpts tumors are genes encoding tumor antigens, com-
ponents of the major histocompatibility complex (MHC) pathways that
process and present antigens or components of the IFN-γ receptor sig-
naling pathway. Tumors lacking antigen processing and presentation
components are commonly found (see Review by Khong and Restifo in
this issue), and tumors have been identified that lack functional expres-
sion of at least three components of the IFN-γ receptor signaling path-
way41 (unpublished data). It is likely that immunologic sculpting of
tumors occurs continuously, but the major effects of this process are
most prominent early when the tumor is perhaps histologically—but
not clinically—detectable. It follows, then, that the immunogenicity of
process because, in its original form, it was thought to function only to
protect the host and to act only at the earliest stages of cellular trans-
formation. Rather, we have proposed the use of the broader term “can-
cer immunoediting” to describe more appropriately the dual host-pro-
tecting and tumor-sculpting actions of the immune system that not only
prevent but also shape neoplastic disease. We envisage the scope of this
process to be very broad such that it can promote complete elimination
of some tumors, generate a nonprotective immune state to others or
favor the development of immunologic anergy, tolerance or indiffer-
ence. We envision important roles for components of both the innate
and adaptive immune systems in this process.
Much work is needed to define the molecular and cellular dynamics
of cancer immunoediting. A proposed basic framework for this process
is illustrated based on recent data from several groups (Figs. 1 and 2).
Although it was not possible to discuss in detail the contributions from
each laboratory that were used in the construction of these models
because of space limitations, we have incorporated key references in
the model descriptions to acknowledge the work of these groups. The
models are presented in the hope that they will stimulate additional

Figure 2. A proposed model a b

for the elimination phase of
the cancer immunoediting
process. (a) The initiation of
the response in which lympho-
cytes that participate in innate
immunity (NKT, NK and γδ T
cells) recognize transformed
cells that have accumulated
above a threshold that has yet
to be defined and are stimulated
to produce IFN-γ. (b) The initial
IFN-γ starts a cascade of innate
immune reactions that involve
(i) the induction of chemokines,
including the angiostatic chemo-
kines (CXCL10 (1P10), CXCL9
(MIG) AND CXCL11 (I-TAC))
c d
that block neovascularization in
the tumor and that also effect
the recruitment of NK cells,
dendritic cells, macrophages and
other immune effector cells to
the tumor site; (ii) an antiprolif-
erative action of IFN-γ on the
developing tumor and (iii) the
activation of cytocidal activity in
macrophages and NK cells
entering the tumor. These
events result in some tumor cell
death by both immunologic and
nonimmunologic mechanisms.
Dead tumor cells or tumor cell
debris (blue squares) are ingest-
ed by dendritic cells and are trafficked to the draining lymph node. (c) Tumor growth is kept in check by the cytocidal activities of NK cells and activated macrophages while
CD4+ and CD8+ T cells that are specific for tumor antigens develop in the draining lymph node. (d) Tumor-specific CD4+ and CD8+ T cells home to the tumor along a
chemokine gradient where they recognize and destroy tumor cells expressing distinctive tumor antigens.Tumor cells (blue); nontransformed cells (gray); dead tumor cells
(white to gray gradient circles surrounded by a dashed black line); lymphocytes, dendritic cells (DC) and macrophages (Mac) are marked and colored appropriately.

996 nature immunology • volume 3 no 11 • november 2002 • www.nature.com/natureimmunology


research aimed at identifying the pathways that lead from cancer
immunosurveillance to tumor escape.
We envisage cancer immunoediting as a result of three processes:
elimination, equilibrium and escape. We call these the three Es of can-
cer immunoediting (Fig. 1). Immunosurveillance occurs during the
elimination process, whereas the Darwinian selection of tumor variants
occurs during the equilibrium process. This in turn can ultimately lead
© 2002 Nature Publishing Group http://www.nature.com/natureimmunology
to escape and the appearance of clinically apparent tumors.
The elimination process encompasses the original concept of cancer
immunosurveillance (Figs. 1a and 2). As such, when it is successful in
deleting the developing tumor, it represents the complete editing process
without progression to the subsequent phases. In the first phase of elim-
ination (Fig. 2a), once solid tumors reach a certain size, they begin to
grow invasively and require an enhanced blood supply that arises as a
consequence of the production of stromagenic and angiogenic pro-
teins77. Invasive growth causes minor disruptions within the surrounding
tissue that induce inflammatory signals leading to recruitment of cells of
the innate immune system (NKT, NK, γδ Τ cells, macrophages and den-
dritic cells) into the site50,78,79. Structures on the transformed cells (either
expressed as a result of the transformation process itself or induced by
the ongoing but limited inflammatory response) are recognized by infil-
trating lymphocytes such as NKT, NK or γδ T cells, which are then stim-
ulated to produce IFN-γ80–82. In the second phase (Fig. 2b), the IFN-γ
that was initially produced may induce a limited amount of tumor death
by means of antiproliferative83 and apopotic84 mechanisms. However, it
also induces the production of the chemokines CXCL10 (interferon-
inducible protein-10, IP-10), CXCL9 (monokine induced by IFN-γ,
MIG) and CXCL11 (interferon-inducible T cell α chemoattractant, I-
TAC) from the tumor cells themselves as well as from surrounding nor-
mal host tissues85–87. At least some of these chemokines have potent
angiostatic capacities and thus block the formation of new blood vessels
within the tumor, which leads to even more tumor cell death88–91. Tumor
cell debris formed as either a direct or indirect consequence of IFN-γ
production at the tumor is then ingested by local dendritic cells, which
home to draining lymph nodes. Chemokines produced during the esca-
lating inflammatory process recruit more NK cells and macrophages to
the site. In the third phase (Fig. 2c), the tumor-infiltrating NK cells and
macrophages transactivate one another by reciprocal production of IFN-
γ and IL-12, and kill more of the tumor by mechanisms involving tumor
necrosis factor–related apoptosis-inducing ligand, perforin and reactive
oxygen and nitrogen intermediates46,92–95. In the draining lymph node, the
newly immigrated dendritic cells induce tumor-specific CD4+ T helper
cells expressing IFN-γ (TH1 cells) that in turn facilitate the development
of tumor-specific CD8+ T cells96–99. In the fourth phase (Fig. 2d), tumor-
specific CD4+ and CD8+ T cells home to the tumor site, where the
cytolytic T lymphocytes destroy the remaining antigen-bearing tumor
cells whose immunogenicities have been enhanced by exposure to local-
ly produced IFN-γ49.
In the equilibrium process (Fig. 1b), the host immune system and any
tumor cell variant that has survived the elimination process enter into a
dynamic equilibrium. In this process, lymphocytes and IFN-γ exert
potent selection pressure on the tumor cells that is enough to contain, but
not fully extinguish, a tumor bed containing many genetically unstable
and rapidly mutating tumor cells. During this period of Darwinian selec-
tion, many of the original escape variants of the tumor cell are destroyed,
but new variants arise carrying different mutations that provide them with
increased resistance to immune attack. It is likely that equilibrium is the
longest of the three processes and may occur over a period of many years.
In the escape process (Fig. 1c), surviving tumor variants that have
acquired insensitivity to immunologic detection and/or elimination
www.nature.com/natureimmunology • november 2002
R EVIEW
through genetic or epigenetic changes begin to expand in an uncontrolled
manner. This results in clinically observable malignant disease that, if left
unchecked, results in the death of the host.
Conclusions and implications
We have summarized here the events that led to the development of the
concept of cancer immunoediting and described the evolution of the con-
cept from its birth in immunosurveillance to its present form. The origi-
nal formulation of the cancer immunosurveillance hypothesis by Burnet
and Thomas was indeed as prescient as it was powerful. Although it was
based on an emerging understanding of the existence of tumor antigens
and the laws of transplantation immunity, it came at a time when not
enough was understood about mouse models of immunodeficiency. This
led to the unwitting use of imperfect animal models to critically test and
prematurely abandon the concept. The concept was resurrected nearly
three decades later by the use of genetically defined mouse models of
complete immunodeficiency coupled with an enhanced understanding of
the molecular nature of tumor antigens. The incorporation of immuno-
surveillance into the cancer immunoediting concept came about by the
finding that the immune system not only protects the host against tumor
development but also can sculpt the immunogenic phenotype of a devel-
oping tumor. Thus, we now recognize a process that has both positive and
negative effects on host–tumor relationships. Clearly, more work is need-
ed to define the process on a molecular and cellular basis.
There are four immediate implications of the cancer immunoediting
concept that directly apply to human cancer. First, we may need to
examine whether immunity plays a role in the development of human
cancers associated with known abnormalities in genes encoding such
proteins as p53, BRCA1, APC (adenomatous polyposis coli) Ras and
others. Second, it will be important to re-examine the carcinogenic
potential of many compounds that have never been tested in experi-
mental animals that are immunodeficient and thus may have been
incorrectly labeled as noncarcinogenic. Third, the relation between
immunologic defects and increased incidences of cancer associated
with aging needs to be explored. Last, we need a way to assess the
extent to which a tumor has been edited.
Perhaps one of the most important contributions of the original
immunosurveillance concept was the furious experimentation that fol-
lowed in its wake. In this respect, we hope for a similar fate for the can-
cer immunoediting concept—new oeuvres framed by the three Es that
test every prediction of this hypothesis and, in eliciting a greater under-
standing of host–tumor interactions, will ultimately have profound
effects on our understanding and treatment of cancer.
Acknowledgments
Supported by grants from the National Cancer Institute (CA43059 and CA76464 to R. D. S.),
the Cancer Research Institute (to R. D. S., H.I and A.B.), the Ludwig Institute for Cancer
Research (to R. D. S.), and the National Institute of Allergy and Infectious Diseases (to R. D. S.
and G. P. D.).We thank V. Shankaran, K. Sheehan,A. Dighe, D. Kaplan, R. Uppaluri, C. Koebel, J.
Bui, E. Stockert, E. Richards, M.White, C.Arthur and C. Brendel for their important roles in
developing the cancer immunoediting concept and for helpful comments during the prepara-
tion of this manuscript.
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