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Published OnlineFirst November 19, 2014; DOI: 10.1158/0008-5472.CAN-14-2440
Cancer
Research
Review
The Inherent Premise of Immunotherapy for Cancer
Dormancy
Masoud H. Manjili
Abstract
Clinical cancer dormancy is evident from the detection of circulating tumor cells in the blood and tissueresiding disseminated tumor cells in the bone marrow of cancer survivors who have been clinically disease
free. Emerging evidence from clinical and preclinical studies suggests that tumor dormancy is a critical step
in the development of both primary cancer and advanced-stage disease. In this review, it is shown that (i)
naturally occurring tumor dormancy precedes occurrence of primary cancer, and (ii) conventional cancer
therapies result in treatment-induced tumor dormancy, which in turn could lead to distant recurrence of
cancer or permanent tumor dormancy, depending on immunogenic status of dormancy. Given that cellular
dormancy is an evolutionary conserved survival mechanism in biologic systems, any stress or cytotoxic
therapy could trigger cellular dormancy. Therefore, a successful cancer therapy is likely to be achieved by
establishing permanent tumor dormancy and preventing distant recurrence of cancer or by eliminating
dormant tumor cells. This could be accomplished by cancer immunotherapy because of the establishment of
long-term memory responses. Cancer Res; 74(23); 1–5. 2014 AACR.
Introduction
In general, primary cancers, breast and prostate cancers in
particular, tend to be responsive to conventional therapies and
do not usually cause mortality in patients. Mortality is a result
of disease recurrence at a distant site to which the disease has
metastasized. This metastatic recurrent disease develops from
residual tumor cells that emerge during conventional cancer
therapies and lay dormant for months, years, or even decades.
There is no effective therapy that could eliminate dormant
tumor cells; neither is there an effective therapy that could
prevent the establishment of tumor dormancy during the
treatment of primary cancer. This is because of the existence
of an evolutionary conserved survival mechanism in the cells
that protects them from environmental hazards, including
radiation, pollution, toxic compounds, and oxidative damage.
There are striking similarities between the concept of tumor
dormancy and the cancer stem cell theory of tumor progression. The tumor dormancy hypothesis similarly predicts that
cellular homeostasis controls cell proliferation by orchestrating the activity of oncogenes and tumor-suppressor genes.
They also overlap in predicting drug resistance and cell-cycle
modifications in tumor cells. However, they differ in that
dormant tumor cells are not limited to stem-like spheroid
Department of Microbiology and Immunology, Virginia Commonwealth
University, Massey Cancer Center, Richmond, Virginia.
Corresponding Author: Masoud H. Manjili, Department of Microbiology
and Immunology, Virginia Commonwealth University, Massey Cancer
Center, 401 College Street, Box 980035, Richmond, VA 23298. Phone:
804-828-8779; Fax: 804-828-8453; E-mail: [email protected]
doi: 10.1158/0008-5472.CAN-14-2440
2014 American Association for Cancer Research.
forming or nonadherent cells, and that cancer stem cells are
not always quiescent and most often continuously give rise to
daughter tumor cells to form cancer. In other words, cancer
stem cells could become dormant, but not all dormant tumor
cells exhibit markers of cancer stem cells. Therefore, dormancy
and stemness could be mutually exclusive. Controversial
reports in the field as to specific markers for the stemness in
different types of cancer and for the characterization of
dormant tumor cells in the circulation of healthy individuals
make a comparative analysis of dormant tumor cells
and cancer stem cells difficult. Advances in our understanding
of tumor dormancy could lead to the development of an
effective therapeutic strategy that will maintain residual tumor
cells in permanent dormancy or eliminate dormant cells
without causing toxicity to normal tissues. In this review, it
is suggested that immunotherapy is a promising strategy that
could target chemo-refractory and radiation-refractory dormant tumor cells to reduce cancer mortality.
Tumor dormancy precedes the establishment of primary
cancer
Biologic systems have an evolutionary conserved regulatory
equipment to keep organs at a precise size such that certain
size is restored if the organ is injured or altered in size. For
instance, if part of the liver is removed, liver cells begin to divide
to the extent that the liver reaches normal size (1). This cellular
homeostasis can be regulated by a balanced cell growth and
apoptosis, which could also protect individuals from progression of nascent transformed cells to cancer. Without such
cellular homeostasis human beings could have become extinct
because environmental hazards continually induce cell transformation. Therefore, malignant cells will not necessarily
establish cancer as long as cellular homeostasis keeps them
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in dormant state. In fact, clinically evident cancers result from
the loss of cellular homeostasis in dormant tumor cells.
Dormant tumor cells have been detected in autopsies of
individuals who were cancer free and died from noncancer
causes. For example, 39% of women autopsied between the
ages 40 and 50 years had indolent malignant cells, whereas the
clinical incidence of breast cancer in the same age range is only
1% (2). Similar occult tumors have been detected for other
types of cancers, including thyroid, prostate, pancreatic cancers, and follicular lymphoma. This seems to be a general
phenomenon, which is called "cancer without disease" (3). This
homeostasis-associated tumor dormancy can be disrupted by
epigenetic changes that regulate angiogenesis. It has been
shown that human tumors can survive in the absence of
angiogenic activity and lay dormant for years without establishing cancer (3). Awakening of dormant tumor cells to
establish primary cancer is associated with downregulation
of angiogenesis inhibitors, which is a late event during carcinogenesis (4). Long-term tumor dormancy for at least 300 days
has also been reported in a mouse model of pregnancy-dependent mammary carcinoma (5). We also reported the presence
of malignant mammary cells before the development of spontaneous mammary carcinoma in FVBN202 transgenic mice (6).
An elegant review article by Bissell and Hines (7) gathered
histologic evidence in support of the existence of tumor
dormancy in cancer-free individuals, some of whom were in
their twenties.
Naturally occurring tumor dormancy does not seem to be
controlled by the immune surveillance only, but rather by an
intrinsic cellular homeostasis that controls cell proliferation.
Tumor immune surveillance is a major component of longlasting tumor dormancy, only when tumor cells are highly
immunogenic, for example, following immunogenic chemotherapy or radiotherapy of primary cancers, as discussed
below, or in virally induced malignancies. This could explain
an increased incidence of viral-driven cancers compared with
spontaneous cancers in immunocompromised patients or in
transplant recipients.
Presence of dormant malignant cells before a cancer is
clinically apparent suggests that many cancer-free individuals may not be cancer-free per se rather they could be
cancer survivors because of harboring dormant malignant
cells, which could establish a primary cancer at any time.
High-risk individuals, including heavy smokers, those with a
family history of cancer or hereditary cancer as well as those
who are exposed to carcinogens in workplace perhaps,
harbor dormant malignant cells that could be detected in
the blood and targeted by an effective therapeutic strategy to
prevent cancer development.
Treatment-induced tumor dormancy and metastatic
recurrence of cancer
Clinical relevance of cancer dormancy following a successful treatment of primary cancer has been proven by the
observation that recipients of organ transplantation developed cancer that could be tracked back to the donors who
were cancer survivors. In addition, circulating tumor cells
(CTC) that are found in the blood as well as tissue-residing
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Cancer Res; 74(23) December 1, 2014
disseminated tumor cells (DTC) that are found in the bone
marrow or other organs have been detected in cancer
survivors. In the case of carcinomas, DTC are capable of
adhering to the tissue culture flask, in vitro, whereas CTCs
are floating cells that are incapable of adherence unless they
can reawaken during tumor relapse.
It has been shown that conventional cancer therapies can
concurrently induce apoptosis and inhibit tumor cell proliferation. This dual function of cancer therapies is apparent
because of the heterogeneity of the tumor cells differentially
responding to treatment, that is, cell death versus growth
inhibition. In fact, residual surviving tumor cells that escape
from chemotherapy- or radiotherapy-induced apoptosis are
likely to be in a state of indolent proliferation and dormancy,
as long as the treatment regimen is continuous. Such
dormant tumor cells become resistant to apoptosis induced
by chemotherapy or radiotherapy, because of being in a
quiescent state (8, 9). CTC have been detected in the blood of
breast cancer survivors several years after successful treatment of primary breast cancer (10). In an in situ model of
tumor recurrence, chemotherapy of breast and prostate
tumors established chemo-resistant dormant tumor cells
that resumed proliferation after drug removal (11). Treatment-induced tumor dormancy is also evident in patients
with platinum-resistant and platinum-responsive ovarian
cancer who eventually develop tumor relapse. In humans,
DTCs that were found to be quiescent were isolated from the
bone marrow after surgical removal of the primary lesion
(12). Sixty-three percent of prostate cancer survivors harbor
DTC in their bone marrow (13). A comparative analysis of
dormant cells in patients with lung cancer (14) and breast
cancer (15) shows that breast CTC and DTC are more
resistant to chemotherapy than dormant lung cancer cells,
because the former contains higher fraction of Ki67-negative
indolent cells. DTCs that can resume proliferation and
establish distant metastasis have been recently reported by
Ghajar and colleagues (16) . Using a mouse model of human
breast cancer metastasis, they showed that DTCs reside on
the endothelium of the microvasculature in the lung, bone
marrow, and brain, which are common metastatic destinations of breast cancer.
Detection of CTC and DTC in patients with cancer is not
limited to those with metastatic disease, as patients with
nonmetastatic cancer or early-stage breast cancer also harbor
CTC (10, 17). Most of these methods for detecting CTC are
based primarily on epithelial markers, which miss out CTCs
that are undergoing epithelial–mesenchymal transition
(EMT). Mesenchymal CTCs are also correlated with poor
prognosis and resistance to chemotherapy. CellSearch is the
only CTC detection method approved by the FDA in patients
with advanced breast, prostate, and colorectal cancers. A
baseline detection of five CTC per 7.5 mL blood or higher can
predict prognosis. In patients with hepatocellular carcinoma,
high incidence of recurrence after hepatectomy or orthotopic
liver transplantation was suggested to be due to the presence of
CTC (18).
Not all patients with dormant CTC or DTC develop recurrence and metastasis. In fact, 50% of DTC-positive patients
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Immunotherapy of Cancer Dormancy
remain disease free. Dormant tumor cells have been detected
in patients with breast cancer 22 years after successful treatment of their primary cancer (10). These observations suggest
that tumor dormancy could be maintained for a long period of
time, even in a state of permanent dormancy, without causing
metastatic recurrence. Therefore, prolonging tumor dormancy
by an effective therapy could overcome tumor relapse. Chemotherapy and radiotherapy are not promising approaches for
prolonging tumor dormancy because dormant tumor cells are
usually resistant to these therapies, and continuous chemotherapy or radiotherapy is not feasible because of their toxicity
against normal cells.
Immunotherapy is a promising approach for tumor
dormancy and elimination of cancer-related mortality
Immune-mediated tumor dormancy has been documented during unintentional transplantation of cancer into
immunocompromised recipients from organ donors who
were in clinical remission (19) or with no clinical history
of cancer (20). Immune-mediated tumor dormancy has also
been demonstrated in the animal model of methylcholanthrene-induced sarcoma (21). This elegant study showed
that immunity can induce and maintain tumor dormancy by
cytostatic and cytolytic functions. This phenomenon was
termed "equilibrium," which is not limited to cancer. Immunity against Mycobacterium tuberculosis is also of cytostatic
nature that keeps the infectious agent in dormant or latent
state, thus protecting the host from active disease. Long
latency before the appearance of AIDS is also evident in the
presence of the immune response. In fact, HIV latency is
influenced by the innate immune response producing cell
restriction factors that inhibit the postintegration steps in
the virus replication cycle. HLA class I–restricted CD8þ T
cells can also modulate HIV reservoirs during natural infection. Sustaining such host-protective immune responses by
booster immunization or novel strategies that could give rise
to memory cells is feasible and safe.
It has been shown that T cells can prevent spontaneous
tumor metastasis by maintaining malignant cells in permanent
dormancy (22). In a murine model of B-cell lymphoma, Farrar
and colleagues reported that IFN-g–producing CD8þ T cells
can establish and maintain tumor dormancy (23). Preclinical
studies show that indolent tumor cells in the bone marrow are
the source of antigenic stimulation that could maintain T-cell
memory pool (24) to keep indolent tumor cells in check. Cancer
vaccines that target tumor blood vessel antigens could also
induce and maintain CD8þ T-cell–dependent tumor dormancy
(25). Immune-mediated tumor dormancy has been suggested
to be the major mechanism for keeping residual tumor cells in
check after the completion of conventional cancer therapies.
Immune-mediated maintenance of tumor dormancy or "equilibrium" could be due to "adaptation," which is the mechanism
by which tumor cells and tumor-reactive immune cells modulate each other without being eliminated, ignored, suppressed, or dominated. In a recent perspective article, the
adaptation model of immunity has been introduced and discussed (26). In fact, anticancer chemotherapies are efficient
primarily when they elicit immunogenic cell death. Some drugs
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that induce immunogenic cell death include but are not limited
to anthracyclines, oxaliplatin, and cyclophosphamide. Immunogenic cell death or dormancy is characterized by a premortem endoplasmic reticulum stress–associated exposure of
calreticulin to the cell membrane and secretion of adenosine
triphosphate (ATP), as well as a postmortem release of highmobility group box 1. Immunogenic dormancy can be established by cancer therapies that induce caspase-dependent
apoptosis rather than caspase-independent mitochondrial
apoptosis. This is because ATP redistribution from lysosomes
to autophagolysosomes and its secretion require the lysosomal
protein LAMP1, which translocate to the cell membrane in a
caspase-dependent manner. In addition, ATP release requires
the opening of pannexin 1 (PANX1) channel, which is triggered
by caspases. Taxol has been shown to induce caspase-independent apoptosis in human cancer cells, yet its antitumor
efficacy can be enhanced when combined with additional
treatments that induce an immune response. A clinically
relevant fractionated dose of radiotherapy has been also shown
to render tumor cells immunogenic by upregulating tumor
MHC class I expression, cross-priming of T cells, and enhancing the immunotherapy of cancer (27). Very recently, we made
a striking observation that dormant mammary tumor cells
established by chemotherapy, in vitro, became chemo-refractory but remained sensitive to apoptosis induced by tumorsensitized T cells (unpublished data). However, in some types
of cancer, tumor antigen loss and/or HLA loss could emerge as
a result of immunoediting, and eventually lead to tumor escape
and relapse. In the FVB mouse model of breast carcinoma, we
showed that neu-specific IFN-g–producing CD8þ T cells concurrently induced apoptosis and indolent tumor dormancy
that eventually led to tumor relapse because of neu antigen loss
(28). Subsequent analysis revealed that such tumor immunoediting was associated with EMT and expression of breast
cancer stem cell markers in the relapsed tumor cells. This
tumor immunoediting was facilitated through the IFN-g/IFN-g
Ra axis such that low, but not high, levels of IFN-g Ra
expression in tumor cells established tumor dormancy, which
in turn led to tumor escape and relapse (29). In these types of
cancer that are prone to immunoediting, tumor escape and
relapse could be overcome by designing immunotherapeutic
strategies that could eliminate rather than maintain dormant
tumor cells. It was reported that natural killer (NK) cells can kill
dormant tumor cells that resist T-cell–induced apoptosis (30).
Thus, a potentially effective immunotherapeutic strategy
should incorporate NKT cells, NK cells and T cells in the
formulation of adoptive cellular therapy rather than focusing
only on CD8þ T cells. Tumor escape from the immune surveillance and subsequent cancer progression could also occur
as a result of the reduced immune function in the elderly or
following transplantation, when immunogenic dormancy is
present. Dormant tumor cells could also lead to active cancer if
they express PD-L1 or other immune checkpoint ligands that
promote T-cell exhaustion. There is no evidence in support of
the role of myeloid-derived–suppressor cells (MDSC) or regulatory T cells (Treg) in compromising T-cell–mediated maintenance of tumor dormancy. In fact, quiescent tumor cells are
not capable of promoting MDSC or Tregs, as no elevation of
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Manjili
these suppressor cells was reported in individuals who harbor
dormant tumor cells.
Conclusion
A hypothetical model of treatment-induced tumor dormancy and recurrence is depicted in Fig. 1. According to this model,
conventional cancer therapies concurrently induce apoptosis
and growth inhibition in tumor cells. The latter effect of
therapies establishes tumor dormancy. Awakening of dormant
tumor cells will depend on treatment-induced immunogenic
dormancy such that nonimmunogenic dormancy leads to early
recurrence after the completion of conventional therapies
whereas immunogenic dormancy induces antitumor immune
responses and leads to prolonged tumor dormancy. Such
prolonged dormancy could be permanent or may lead to tumor
escape and late recurrence as a result of immunoediting,
altered immune responses during aging, or immune suppression following organ transplantation. Levels of tumor IFN-g Ra
are a key determinant of tumor escape and relapse or relapsefree survival during immunogenic tumor dormancy, which is
usually the case in viral-driven malignancies or following
immunogenic chemotherapy or radiotherapy of primary
cancers.
Because dormant tumor cells are resistant to chemotherapy
or radiotherapy because of being quiescent, they remain
sensitive to immunotherapy because of becoming immunogenic and also being outnumbered by antitumor T cells.
Reprogramming of endogenous antitumor immune responses
toward memory phenotypes could keep dormant tumor cells
in check without continuous and potentially toxic therapies,
thereby inducing permanent tumor dormancy and overcoming
Heterogenous tumor
Apoptosis
Growth inhibition
Non-immunogenic
dormancy
Cancer therapies
Immunogenic
dormancy
Maintain tumor dormancy
Completion of
cancer therapy
Early recurrence
IFN-γ Rαlow
IFN-γ Rαhigh
Elimination
Immune response
Figure 1. A hypothetical model of
treatment-induced tumor
dormancy and recurrence.
Heterogeneity of tumor cells results
in differential responses to the
treatment by cell death or growth
inhibition and dormancy. Outcome
of cancer treatment will depend on
nonimmunogenic dormancy,
leading to early tumor relapse, or
immunogenic dormancy, leading to
the elimination of tumor dormancy,
permanent maintenance of tumor
dormancy, or tumor escape and
relapse, depending on the status of
tumor IFN-g Ra.
Late recurrence
Tumor escape
No dormancy
Permanent
dormancy
Recurrence-free
Tumor recurrence
© 2014 American Association for Cancer Research
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Immunotherapy of Cancer Dormancy
tumor escape. Such immunotherapeutic strategy could also be
used in high-risk individuals who harbor CTC or DTC without a
clinically apparent cancer, to prevent development of a primary cancer. In the long-term, cancer immunotherapy could
be further improved to eliminate dormant tumor cells when
combined with chemotherapy along with the blockade of
pathways involved in tumor dormancy. However, breaking
tumor dormancy to render them sensitive to chemotherapy
is a risky approach compared with establishing permanent
dormancy.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Received August 18, 2014; revised September 15, 2014; accepted September 15,
2014; published OnlineFirst November 19, 2014.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Ibirogba SB, Spearman CW, Mall A, Shepherd E, Lotz Z, Tyler M, et al.
Restoration of liver mass after partial hepatectomy–implications for
living donor liver transplantation. S Afr J Surg 2005;43:70–2.
Nielsen M, Thomsen JL, Primdahl S, Dyreborg U, Andersen JA. Breast
cancer and atypia among young and middle-aged women: a study of
110 medicolegal autopsies. Br J Cancer 1987;56:814–9.
Folkman J, Kalluri R. Cancer without disease. Nature 2004;427:787.
Almog N, Ma L, Raychowdhury R, Schwager C, Erber R, Short S, et al.
Transcriptional switch of dormant tumors to fast-growing angiogenic
phenotype. Cancer Res 2009;69:836–44.
Gattelli A, Cirio MC, Quaglino A, Schere-Levy C, Martinez N, Binaghi M,
et al.Progression of pregnancy-dependent mouse mammary tumors
after long dormancy periods. Involvement of wnt pathway activation.
Cancer Res 2004;64:5193–9.
Kmieciak M, Morales JK, Morales J, Bolesta E, Grimes M, Manjili MH.
Danger signals and nonself entity of tumor antigen are both required for
eliciting effective immune responses against HER-2/neu positive
mammary carcinoma: implications for vaccine design. Cancer Immunol Immunother 2008;57:1391–8.
Bissell MJ, Hines WC. Why don't we get more cancer? A proposed role
of the microenvironment in restraining cancer progression. Nat Med
2011;17:320–9.
Naumov GN, Townson JL, MacDonald IC, Wilson SM, Bramwell VH,
Groom AC, et al. Ineffectiveness of doxorubicin treatment on solitary
dormant mammary carcinoma cells or late-developing metastases.
Breast Cancer Res Treat 2003;82:199–206.
Jinno-Oue A, Shimizu N, Hamada N, Wada S, Tanaka A, Shinagawa M,
et al.Irradiation with carbon ion beams induces apoptosis, autophagy,
and cellular senescence in a human glioma-derived cell line. Int J
Radiat Oncol Biol Phys 2010;76:229–41.
Meng S, Tripathy D, Frenkel EP, Shete S, Naftalis EZ, Huth JF, et al.
Circulating tumor cells in patients with breast cancer dormancy. Clin
Cancer Res 2004;10:8152–62.
Li S, Kennedy M, Payne S, Kennedy K, Seewaldt VL, Pizzo SV, et al.
Model of tumor dormancy/recurrence after short-term chemotherapy.
PLoS ONE 2014;9:e98021.
Suzuki M, Mose ES, Montel V, Tarin D. Dormant cancer cells retrieved
from metastasis-free organs regain tumorigenic and metastatic potency. Am J Pathol 2006;169:673–81.
Morgan TM, Lange PH, Porter MP, Lin DW, Ellis WJ, Gallaher IS, et al.
Disseminated tumor cells in prostate cancer patients after radical
prostatectomy and without evidence of disease predicts biochemical
recurrence. Clin Cancer Res 2009;15:677–83.
Hou JM, Krebs MG, Lancashire L, Sloane R, Backen A, Swain RK, et al.
Clinical significance and molecular characteristics of circulating tumor
cells and circulating tumor microemboli in patients with small-cell lung
cancer. J Clin Oncol 2012;30:525–32.
Muller V, Stahmann N, Riethdorf S, Rau T, Zabel T, Goetz A, et al.
Circulating tumor cells in breast cancer: correlation to bone marrow
micrometastases, heterogeneous response to systemic therapy and
low proliferative activity. Clin Cancer Res 2005;11:3678–85.
www.aacrjournals.org
16. Ghajar CM, Peinado H, Mori H, Matei IR, Evason KJ, Brazier H, et al.The
perivascular niche regulates breast tumour dormancy. Nat Cell Biol
2013;15:807–17.
17. Lucci A, Hall CS, Lodhi AK, Bhattacharyya A, Anderson AE, Xiao L,
et al.Circulating tumour cells in non-metastatic breast cancer: a prospective study. Lancet Oncol 2012;13:688–95.
18. Xu W, Cao L, Chen L, Li J, Zhang XF, Qian HH, et al.Isolation of
circulating tumor cells in patients with hepatocellular carcinoma
using a novel cell separation strategy. Clin Cancer Res 2011;17:
3783–93.
19. Kauffman HM, McBride MA, Delmonico FL. First report of the united
network for organ sharing transplant tumor registry: donors with a
history of cancer. Transplantation 2000;70:1747–51.
20. Myron Kauffman H, McBride MA, Cherikh WS, Spain PC, Marks WH,
Roza AM. Transplant tumor registry: donor related malignancies.
Transplantation 2002;74:358–62.
21. Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ, Old LJ, et al.
Adaptive immunity maintains occult cancer in an equilibrium state.
Nature 2007;450:903–7.
22. Romero I, Garrido C, Algarra I, Collado A, Garrido F, Garcia-Lora AM. T
lymphocytes restrain spontaneous metastases in permanent dormancy. Cancer Res 2014;74:1958–68.
23. Farrar JD, Katz KH, Windsor J, Thrush G, Scheuermann RH, Uhr JW,
et al.Cancer dormancy. VII. A regulatory role for CD8þ T cells and IFNgamma in establishing and maintaining the tumor-dormant state.
J Immunol 1999;162:2842–9.
24. Mahnke YD, Schwendemann J, Beckhove P, Schirrmacher V. Maintenance of long-term tumour-specific T-cell memory by residual dormant tumour cells. Immunology 2005;115:325–36.
25. Zhao X, Bose A, Komita H, Taylor JL, Chi N, Lowe DB, et al.Vaccines
targeting tumor blood vessel antigens promote CD8(þ) T-cell–dependent tumor eradication or dormancy in HLA-A2 transgenic mice.
J Immunol 2012;188:1782–8.
26. Manjili MH. The adaptation model of immunity. Immunotherapy
2014;6:59–70.
27. Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS,
Formenti SC, et al.Fractionated but not single-dose radiotherapy
induces an immune-mediated abscopal effect when combined with
anti-CTLA-4 antibody. Clin Cancer Res 2009;15:5379–88.
28. Kmieciak M, Knutson KL, Dumur CI, Manjili MH. HER-2/neu antigen
loss and relapse of mammary carcinoma are actively induced by Tcell–mediated anti-tumor immune responses. Eur J Immunol
2007;37:675–85.
29. Kmieciak M, Payne KK, Wang XY, Manjili MH. IFN-gamma ralpha is
a key determinant of CD8þ T cell-mediated tumor elimination or
tumor escape and relapse in FVB mouse. PLoS ONE 2013;8:
e82544.
30. Saudemont A, Jouy N, Hetuin D, Quesnel B. NK cells that are activated
by CXCL10 can kill dormant tumor cells that resist CTL-mediated lysis
and can express B7-H1 that stimulates T cells. Blood 2005;105:
2428–35.
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The Inherent Premise of Immunotherapy for Cancer
Dormancy
Masoud H. Manjili
Cancer Res Published OnlineFirst November 19, 2014.
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