[Downloaded free from http://www.jofs.in on Friday, January 5, 2018, IP: 157.48.122.

209]

Review Article

A Review on Tumor Immunology

Abstract Sri Lalitha Kaja,

The ability of immune system to detect and destroy the altered/abnormal cells may inhibit the S. V. N. Sasi Kiran,
development of various cancers. The immune system had been proposed as a tactic in sustaining Kiran Kumar
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 Kattapagari,
of modulating the oncogenic process. The failure of host’s immunological responses against tumor Ravi Teja Chitturi,
growth and dissemination implicated that both immunologic and nonimmunologic factors may work S. Deepika
together to affect tumorigenesis. Hence, understanding the aspects pertaining to tumor immunology Chowdary,
which deals with the complex interactions between the host’s immune system and neoplasm Baddam Venkata
is essential. The current review focuses on the aspects concerned with tumor immunology, steps
involved, and cancer immunotherapy as a probable therapeutic tool. Ramana Reddy
Department of Oral Pathology
Keywords: Cancer, immune escape, immunosurveillance, immunoediting, immunology, tumor and Microbiology, SIBAR
Institute of Dental Sciences,
Takkellapadu, Guntur,
Introduction Tumors progress even in immunologically Andhra Pradesh, India
competent hosts, as they manage to escape
Tumor immunology is the “study of the
from the immune system. The escape process
complex interaction between a human host
is attributed to the inability of immune cells
and a neoplasm, which unless adequately
to develop an effective antitumor response or
treated causes the death of the host.”
to the inhibition of functions of the immune
Frequent failure of the immunologic
system by tumor‑derived factors.[3]
responses of the host to restrict tumor
growth and dissemination led to the The current review focuses on the aspects
realization that both immunologic and concerned with tumor immunology.
nonimmunologic factors may act in concert Tumor immunology includes:
to affect tumorigenesis. Numerous studies • Immunosurveillance
have focused on the immune system as • Immunoediting
a tactic in sustaining nonneoplastic state • Immune evasion.
and also for the possibility of developing
cancer immunotherapy. Although under Cancer Immunosurveillance
some circumstances, immune system exerts
The three primary roles of the immune
a protective role; under other conditions, it
system in the prevention of tumors are as
could be damaging or irrelevant in terms of
follows:
modulating the oncogenic process.[1]
• First, the immune system by eliminating Address for correspondence:
Paul Ehrlich was the first one to propose or suppressing viral infections, protects Dr. Sri Lalitha Kaja,
that “the immune system could repress the host from tumors induced by viruses Department of Oral Pathology
and Microbiology, SIBAR
a potentially overwhelming frequency of • Second, by the elimination of pathogens Institute of Dental Sciences,
carcinomas” which was found to be a key for and prompt resolution of inflammation, Takkellapadu, Guntur ‑ 522 509,
the cancer immunosurveillance hypothesis. it prevents the establishment of an Andhra Pradesh, India.
Despite tumor immunosurveillance, inflammatory environment that is E‑mail: srilalitha_kaza@yahoo.
com
development of tumors can occur even in conducive to tumorigenesis
the presence of functioning immune system, • Third, the immune system could
and hence an updated concept of tumor specifically identify and eliminate tumor Access this article online
immunoediting was proposed which gives cells by the expression of tumor‑specific
Website: www.jofs.in
a more complex explanation for the role of antigens or molecules that are induced
DOI: 10.4103/0975-8844.207949
immune system in tumor development.[2] by cellular stress.
Quick Response Code:

This is an open access article distributed under the terms of the

Creative Commons Attribution-NonCommercial-ShareAlike 3.0
License, which allows others to remix, tweak, and build upon the
work non-commercially, as long as the author is credited and the
new creations are licensed under the identical terms.
For reprints contact: reprints@medknow.com
How to cite this article: Kaja SL, Kiran SS,
Kattapagari KK, Chitturi RT, Chowdary SD,
Reddy BV. A review on tumor immunology. J Orofac
Sci 2017;9:7-15.

© 2017 Journal of Orofacial Sciences | Published by Wolters Kluwer - Medknow 7

[Downloaded free from http://www.jofs.in on Friday, January 5, 2018, IP: 157.48.122.209]
Kaja, et al.: Tumor immunology
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.”[4]
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.[2]
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.”[5]
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.[6] 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.[7,8]
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.[8]
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.[9]
Cancer immunosurveillance represents only one dimension
of the complex interaction between the immune system and
8 Journal of Orofacial Sciences | Volume 9 | Issue 1 | January-June 2017
cancer.[2] 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.[10]
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.[3] 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.[11]
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.[2]
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.[12]
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:[13]
• Elimination
• Equilibrium
• Escape.
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.[14]
Elimination
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
[Downloaded free from http://www.jofs.in on Friday, January 5, 2018, IP: 157.48.122.209]
Kaja, et al.: Tumor immunology
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).[14]
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.[2] 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.[14]
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.[15] 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
Journal of Orofacial Sciences | Volume 9 | Issue 1 | January-June 2017
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.[2]
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.[14]
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.
Equilibrium
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.[2,16]
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
9
[Downloaded free from http://www.jofs.in on Friday, January 5, 2018, IP: 157.48.122.209]
Kaja, et al.: Tumor immunology
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.[4]
Escape
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.[17]
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.[18]
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.[14]
10
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.[19] Although
tumors possess tumor rejection antigens, they are capable
of escaping destruction by host immunity which indicates
that some form of immune evasion occurs.[20] 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.[21]
Tumors elaborate assembly of tricks to fool the immune
system in general to avoid recognition.
i. They either hide from immune cells thus avoiding
recognition
ii. They proceed to disable or eliminate immune cells.[22]
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.[22]
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.[23] Tumors
frequently misprocessed with TAA, where the immunogenic
peptides cannot be made. These immunogenic peptides
Journal of Orofacial Sciences | Volume 9 | Issue 1 | January-June 2017
[Downloaded free from http://www.jofs.in on Friday, January 5, 2018, IP: 157.48.122.209]

Kaja, et al.: Tumor immunology

cannot include in Human leukocytic antigen class I. In Table 1: Tumor factors modulating the immune cells
such cases, trimolecular HLA class I‑chain‑β2m‑peptide Factor-Modulatory mechanism
is absent from the tumor cell surface. The peptide‑HLA The TNF family ligands:
molecule complex thus formed cannot be recognized by the Induce leukocyte apoptosis
cytotoxic T‑lymphocytes.[24] via the TNF family receptors
FasL Fas
Another aberration in tumor cells involves the
TRAIL TRAIL‑R
downregulated expression of costimulatory molecules on
TNF TNFR1
the cell surface that are essential for producing interactions
Small molecules
with T‑lymphocytes. Decreased expression of costimulatory
Prostaglandin E2 Inhibits leukocyte functions
molecules such as B7 family on tumor cells could lead to
through increased cAMP
unresponsiveness based on MHC Class I restricted antigen
Histamine Inhibits leukocyte functions
presentation without transmission of the costimulatory through increased cAMP
signals that are critical for the activation of leukocytes.[25] Epinephrine Inhibits leukocyte functions
Tumors either produce or induce factors which in turn through increased cAMP
modulate the functions of immune cells or induce apoptosis INOS Promotes or inhibits Fas‑mediated
apoptosis by regulation of no
of the immune cells. These factors include a broad range of
levels
biological effector molecules such as [Table 1]:[22]
H 2O 2 Has pro‑oxidant activity, increases
• Several distinct receptor–ligand systems cAMP levels, causes apoptosis in
• Small molecular species NK cells, inhibits tumor‑specific
• Cellular enzymes CTL
• Soluble cell components Enzymes
• Cytokines/chemokines. Indoleamine Suppresses T‑cell responses
2,3‑dioxygenase
This diversity indicates that tumors are incredible in their
Arginase I Impairs T‑cell functions, decreases
ability to defend or debilitate the host immune responses.
chain expression
Mechanisms of tumor immune escape Cytokines
TGF‑β Inhibits perforin and granzyme
Mechanisms responsible for immune cell dysfunction in mRNA expression; inhibits
cancer are numerous. The escape from tumor immunity can lymphocyte proliferation
be achieved in three principally distinct ways [Table 2]. IL‑10 Inhibits production of IL‑1, IFN‑γ,
They are by: IL‑12 and TNF‑α
• Lack of recognition by means of loss or alteration of GM‑CSF Promotes expansion
molecules which are important for the recognition and of immunosuppressive
activation of the immune system tumor‑associated macrophages
• Lack of susceptibility, i.e.,  escape from the effector Tumor‑associated Inhibit IL‑2 dependent lymphocyte
mechanisms of cytotoxic lymphocytes gangliosides proliferation or induce apoptotic
• Induction of immune dysfunction.[26] signals
TNF: Tumor necrosis factor, TRAIL‑R: Tumor necrosis
These mechanisms render the tumor cells less recognizable factor alpha‑inducing ligand‑receptor, TNFR1: Tumor
by NK cells and T‑cells and also make them less susceptible necrosis factor receptor 1, TGF: Transforming growth factor,
to the effector molecules of the immune system. There GM‑CSF: Granulocyte‑macrophage colony‑stimulating factor,
is a continuous shaping of the tumor cell clones by both IFN: Interferon, IL: Interleukin, CTL: Cytolytic T lymphocytes,
nonimmune and immunosurveillance mechanisms. This NK: Natural killer, INOS: Inducible nitric oxide synthase,
sculpting process often extends for longer periods, probably cAMP: Cyclic adenosine monophosphate
many years and perhaps for decades.
and relies on glycolysis to produce energy which is called
Immune escape mechanisms related to tumor metabolic
the Warburg effect. Warburg in 1920 found that even in
changes
the presence of ample oxygen, the tumor cells prefer to
Tumors confront the adverse environment in two contexts. metabolize glucose by glycolysis, a metabolic pathway
First, the developing tumors must acquire nutrients to that converts glucose into pyruvate.[41] Pyruvate is reduced
ensure their rapid growth, and second, they must escape to lactic acid by fermentation. Although it is less efficient
from the attack by host immune system. Recent studies for producing adenosine triphosphate, it is quicker than
suggest that tumor cell metabolism plays a pivotal role in OXPHOS and confers a selective advantage to rapidly
tumor immune escape. growing tumor cells. This was related to low oxygen
Tumor cell metabolism avoids the activities of concentration in the inner region of nascent tumors that
mitochondria and oxidative phosphorylation (OXPHOS) progressively become distanced from the vasculature
Journal of Orofacial Sciences | Volume 9 | Issue 1 | January-June 2017 11
[Downloaded free from http://www.jofs.in on Friday, January 5, 2018, IP: 157.48.122.209]

Kaja, et al.: Tumor immunology

Table 2: Mechanisms responsible for immune escape by tumors

Mechanism-Pathway for Immune escape
Lack of recognition[26]
Alterations in the antigen processing Mutations and/or deletions of one or several genes encoding components of the antigen
and presentation pathway[27,28] processing machinery
Complete loss of HLA molecules
Absence of peptide and β2 microglobulin, needed for MHC class I molecule
Mutations of proteasomal subunits such as LMP‑2 and LMP‑7 as well as of the peptide
transporters such as TAP‑1 and TAP‑2
Loss of antigenic variants[29] Simultaneous loss of antigen and HLA class I
Decreased activation of NK cells Structural alterations ‑ total, allelic, or locus‑specific loss of MHC class I heavy chain;
and T‑cells by downregulating B2‑microglobulin deletions, rearrangements, or mutations; transporter associated with antigen
MHC[30,31] processing mutations
Dysregulation‑methylation and acetylation; transcriptional downregulation; posttranscriptional
downregulation; deficient IFN‑γ signal transduction
Enhanced negative signaling and Ectopic expression of nonclassical HLA molecule such as HLA‑G inhibits NK cell function by
counter attack[26,32‑34] binding to inhibitory receptors including the LILRB1
HLA‑G also shuts down the production of IFN‑γ and Fcγ receptor‑mediated activation of LIR‑1
expressing macrophages
Via a Fas–FasL‑dependent mechanism, HLA‑G1 were known to induce apoptosis of CD8+
T‑cells. Nonclassical HLA‑E and HLA‑F molecules, as well as alleles of HLA‑C, were shown
to induce apoptosis of NK cells. Tumor cells also secrete FasL‑bearing vesicles that induce
lymphocyte apoptosis known as “Fas‑counterattack”
Suppression of antitumor responses Cell‑to‑cell contact‑independent soluble factors, such as immunoinhibitory cytokines
by TRegs cells[21,35] (IL‑10 and TGF‑β) or adenosine
The cell contact‑dependent accumulation of cAMP in target cells or target cell death mediated by
perforin/granzyme B or death receptor‑ligand interactions
The competition for IL‑2, between TRegs and responders leading to death by starvation of
responder cells or for CTLA‑4/B7 co‑stimulation between TRegs and antigen‑presenting cells,
depriving responder cells of co‑stimulatory signaling necessary for proliferation
Lack of susceptibility
Induction and regulation of Tumor cells overexpress antiapoptotic molecules such as bcl‑2 thereby resists apoptosis and
apoptosis[26,36] hence escape from both nonimmune and immune surveillance mechanisms
Escaping death receptor Tumors escape death receptor signaling by overexpression of flip and also by release of soluble
signaling[26,37,38] factors such as Fas receptors, decoy receptors, and FasL
Presence of decoy death receptors (TRAIL‑R3 and TRAIL‑R4) lacking the intracellular domain
Missense mutations in the Fas gene leading to decreased expression or expression of
nonfunctional receptors
Metalloproteases such as matrix metalloprotease‑7 by cleaving Fas thereby decreasing the
surface expression of Fas and rendering the tumor resistant to FasL‑mediated apoptosis
Alterations in the FADD and of caspase ten by inactivation mutations
Escape from perforin and granzyme Tumors overexpress the serine PI‑9 that inhibits Granzyme B
B‑induced apoptosis[26] Cathepsin B, a cysteine proteinase is that inactivates perforin is overexpressed by tumors
Failure of IFN‑γ to induce the platelet activating factor receptor could confer tumor cell escape
from perforin‑mediated killing
Tumor‑induced immune suppression
Chronic inflammation[39,40] Tumors gain a growth advantage by secreting immunosuppressive cytokines or specifically
recruiting TRegs and MSC that dampen immune reactivity
Decreased Th1 cytokine production and poor cytolytic capacity of tumor infiltrating lymphocytes
and peripheral blood lymphocytes. This is associated with decreased levels of signaling
molecules such as p56, p59, ZAP70, JAK3, STAT‑5 and block of nuclear factor‑κβ which helps
in immune escape of the tumors
TRAIL: Tumor necrosis factor alpha‑inducing ligand, TGF: Transforming growth factor, IFN: Interferon, IL: Interleukin, NK: Natural killer,
TRegs: T regulatory, HLA: Human leukocyte antigen, TAP: Transporter associated with antigen presentation, MHC: Major histocompatibility,
Th: T‑helper cells, LMP: Low molecular mass polypeptides, CTLA‑4: Cytotoxic T‑lymphocyte‑associated antigen‑4, FADD: Fas‑associated
death domain, PI: Protease inhibitor, MSC: Myeloid suppressor cells, LILRB1: Leukocyte immunoglobulin‑like receptor B1, cAMP: Cyclic
adenosine monophosphate, LIR: Leukocyte immunoglobulin‑like receptor
12 Journal of Orofacial Sciences | Volume 9 | Issue 1 | January-June 2017
[Downloaded free from http://www.jofs.in on Friday, January 5, 2018, IP: 157.48.122.209]
Kaja, et al.: Tumor immunology
thereby resulting in a metabolic shift from OXPHOS to
fermentation.[42]
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.[43] 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.[44]
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.[45]
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
Journal of Orofacial Sciences | Volume 9 | Issue 1 | January-June 2017
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.[44]
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.[46]
Stimulation of active host immune responses
• Vaccination using tumor cells and antigens:
o 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:
o 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:
o 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:
o It is the transfer of cultured immune cells having
antitumor reactivity into a tumor‑bearing host
• Therapy with antitumor antibodies:
o Tumor‑specific monoclonal antibodies
o 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
13
[Downloaded free from http://www.jofs.in on Friday, January 5, 2018, IP: 157.48.122.209]
Kaja, et al.: Tumor immunology
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
Nil.
Conflicts of interest
There are no conflicts of interest.
References
1. Siegel BV. Tumor immunity. An overview. Am J Pathol
1978;93:515‑24.
2. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer
immunoediting: From immunosurveillance to tumor escape. Nat
Immunol 2002;3:991‑8.
3. Finn OJ. Human tumor antigens, immunosurveillance, and
cancer vaccines. Immunol Res 2006;36:73‑82.
4. Swann JB, Smyth MJ. Immune surveillance of tumors. J Clin
Invest 2007;117:1137‑46.
5. Burnet FM. Cancer; a biological approach. I. The processes of
control. Br Med J 1957;1:841‑7.
6. Thomas L. On immunosurveillance in human cancer. Yale J Biol
Med 1982;55:329‑33.
7. Burnet FM. The concept of immunological surveillance. Prog
Exp Tumor Res 1970;13:1‑27.
8. Burnet M. Immunological factors in the process of
carcinogenesis. Br Med Bull 1964;20:154‑8.
9. Klein G, Klein E. Surveillance against tumors – Is it mainly
immunological? Immunol Lett 2005;100:29‑33.
10. Laroye  GJ. How efficient is immunological surveillance against
cancer and why does it fail? Lancet 1974;1:1097‑100.
11. Dunn GP, Old LJ, Schreiber RD. The immunobiology of
cancer immunosurveillance and immunoediting. Immunity
2004;21:137‑48.
12. Penn I. Tumors of the immunocompromised patient. Annu Rev
Med 1988;39:63‑73.
13. Sengupta N, MacFie TS, MacDonald TT, Pennington D,
Silver AR. Cancer immunoediting and spontaneous tumor
regression. Pathol Res Pract 2010;206:1‑8.
14. Dunn GP, Old LJ, Schreiber RD. The three Es of cancer
immunoediting. Annu Rev Immunol 2004;22:329‑60.
15. 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.
16. Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in
human cancers. Nature 1998;396:643‑9.
17. Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural
innate and adaptive immunity to cancer. Annu Rev Immunol
2011;29:235‑71.
18. Khong HT, Restifo NP. Natural selection of tumor variants
in the generation of tumor escape phenotypes. Nat Immunol
2002;3:999‑1005.
19. Villalba M, Rathore MG, Lopez- Royuela N, Krzywinska E,
14
Garaude J. From tumor cell metabolism to tumor immune
escape. Int J Biochem Cell Biol 2013;45:106-13.
20. Mitra R, Singh S, Khar A. Antitumour immune responses. Expert
Rev Mol Med 2003;5:1‑19.
21. Whiteside TL. Tricks tumors use to escape from immune control.
Oral Oncol 2009;45:e119‑23.
22. Whiteside TL. Immune suppression in cancer: Effects on
immune cells, mechanisms and future therapeutic intervention.
Semin Cancer Biol 2006;16:3‑15.
23. 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.
24. 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.
25. 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.
26. Malmberg KJ, Ljunggren HG. Escape from immune‑ and
nonimmune‑mediated tumor surveillance. Semin Cancer Biol
2006;16:16‑31.
27. 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.
28. Seliger B. Strategies of tumor immune evasion. BioDrugs
2005;19:347‑54.
29. 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.
30. 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.
31. 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.
32. 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.
33. 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.
34. Restifo NP. Not so Fas: Re‑evaluating the mechanisms of
immune privilege and tumor escape. Nat Med 2000;6:493‑5.
35. Roncarolo MG, Bacchetta R, Bordignon C, Narula S, Levings MK.
Type 1 T regulatory cells. Immunol Rev 2001;182:68‑79.
36. 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.
37. 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.
38. Hallermalm K, De Geer A, Kiessling R, Levitsky V, Levitskaya J.
Autocrine secretion of Fas ligand shields tumor cells from
Journal of Orofacial Sciences | Volume 9 | Issue 1 | January-June 2017
[Downloaded free from http://www.jofs.in on Friday, January 5, 2018, IP: 157.48.122.209]

Kaja, et al.: Tumor immunology

Fas‑mediated killing by cytotoxic lymphocytes. Cancer Res
2004;64:6775‑82.
39. Malmberg KJ. Effective immunotherapy against cancer:
A question of overcoming immune suppression and immune
escape. Cancer Immunol Immunother 2004;53:879‑92.
40. 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.
41. Warburg O. On respiratory impairment in cancer cells. Science
1956;124:269‑70.
42. 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.
43. 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.
44. van der Bruggen P, Van den Eynde BJ. Processing and
presentation of tumor antigens and vaccination strategies. Curr
Opin Immunol 2006;18:98‑104.
45. 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.
46. Abbas AK, Lichtman AH. Cellular and Molecular Immunology.
5th ed. Philadelphia: Elsevier Saunders; 2005. p. 391‑410.

Journal of Orofacial Sciences | Volume 9 | Issue 1 | January-June 2017 15