Immunosurveillance and Oral Cancer
Gokul
S, Sapna G
Gokul S, Lecturer, Oral Pathology and Microbiology, YMT Dental College and
Hospital, Institutional Area, Sector 4, Kharghar, 410210, Navi Mumbai, India
Sapna G, Lecturer, Periodontics, Nair Hospital Dental College, Mumbai Central,
400018, Mumbai, India
Correspondence to: Gokul S, Lecturer, Oral Pathology and Microbiology, YMT Dental
College and Hospital, Institutional Area, Sector 4, Kharghar, 410210, Navi
Mumbai, India
Email: drgokuls@gmail.com
Telephone: +22-27744429
Fax: + 22-27744427
Received: January 15, 2014
Revised: February 2, 2014
Accepted: February 9, 2014
Published online: May 18, 2014
ABSTRACT
The immune system of the body plays an important role in human
tumorigenesis. Literature data over the past several decades has provided
evidence for the same. The ideas concerning the activities of the host immunity
have evolved from the initial immunosurveillance concept which describes the
anti-tumorigenic effects of the immune system to the more recently proposed
immunoediting concept. The concept of tumor immunoediting describes the dual
action of immune system in acting as tumor scavengers as well as tumor
promoters. This has been described based on three stages of tumor immunoediting
namely elimination, equilibrium and escape. Oral squamous cell carcinoma (OSCC)
is a multifactorial disease caused chiefly by tobacco and its products which
exhibit several genetic and molecular aberrations. Among the various hallmarks
of oral carcinogenesis is the role of immune system to destroy the tumor cells
as well as the ability of the tumor cells to evade the host immune system.
Various cells such as mast cells, tumor necrosis factor alpha (TNF-α),
eosinophils, macrophages and interferon-γ have been found to be involved in
OSCC. This review encompasses the basics of immunosurveillance and
immunoediting concept with a note on the different cellular mediators of immune
system as pertaining to OSCC.
© 2014 ACT. All rights reserved.
Key words: Immunosurveillance; Immunoediting;
Oral cancer
Gokul S, Sapna G. Immunosurveillance
and Oral Cancer. Journal of Tumor 2014; 2(5): 136-141 Available from:
URL: http://www.ghrnet.org/index.php/JT/article/view/679
INTRODUCTION
Carcinogenesis is a
complex multistep process in which genetic events within signal transduction
pathways that govern the normal cellular physiology are quantitatively or
qualitatively altered[1]. Oral squamous cell carcinoma (OSCC)
develops as a consequence of multiple molecular events in many chromosomes and
genes. The consequence of this damage is cell dysregulation with disruption in
cell signaling, the cell growth cycle and/or mechanisms to repair cell damage
or eliminate the dysfunctional cells[2]. The process of
carcinogenesis involves seven fundamental changes in cell physiology that
determines malignant phenotype. These includes self-sufficiency in growth signals,
insensitivity to growth inhibitory signals, evasion of apoptosis, defects in
DNA repair, limitless replicative potential, sustained angiogenesis and ability
to invade and metastasize[3]. Another important hallmark identified
for tumor development is the acquired capacity of developing tumors to escape
immune control of the body. This formed the basis of immunoediting hypothesis
of tumor development.
The immune system represents
a complex assortment of interacting cells and proteins which can be broadly
divided into innate and adaptive types[4]. Innate immunity refers to
defense mechanisms that are present even before infection and forms the first
line of defense. The major components of innate immunity are epithelial
barriers, phagocytic cells, natural killer cells and several plasma proteins
including proteins of complement system. Adaptive immunity consists of
mechanisms that are stimulated by microbes and also recognize distinct antigens
by lymphocytes carrying specific receptors. Cells of the immune system are
primarily involved in adaptive immunity. Within the lymphoid system two groups
of cells mainly T-lymphocytes (cell-mediated immunity) and B-lymphocytes
(humoral immunity) are involved[4,5].
Literature data accumulated
over the years suggest the development of immune response to various human
cancers by the host system. Humans suffering from cancers are known to
spontaneously develop specific adaptive immune responses to tumor antigens
through CD8 T-cells. The innate arm of the immune system may also discriminate
between tumor cells and normal cells through MHC class I chain related proteins
A and B which serve as ligands for NKG2D and T-cell receptors present on cell
of innate immune system[6].
The role of immune system in
human carcinogenesis is often regarded as a double edged sword wherein the
body’s immune system is known to nullify the harmful effects of cancer cell
proliferation while it may also promote tumor growth. Data available in the
literature provides evidence towards the dual action of the host immune system.
Recent advances in identifying various players of immune system has contributed
to its current understanding that has also helped in evolution of
immunotherapeutic agents as a treatment modality for cancer. This review
discusses the historical perspectives, mechanism and current understanding of
concepts concerning the role of immune system in carcinogenesis with additional
emphasis on its role in oral squamous cell carcinoma.
HISTORY
The original
description of the idea that the immune system could repress a potentially
overwhelming frequency of carcinomas was envisaged by Paul Ehrlich in 1909[7].
As the understanding of immunology expanded, Burnett and Thomas in 1957
proposed the immunosurveillance theory speculating that the immune system was
capable of destroying growing malignancies[8]. The theory speculated
that the lymphocytes acted as sentinels in recognizing and eliminating
continuously arising, nascent transformed cell[9]. Subsequent
experiments however disproved this concept based on the findings in athymic
nude mice available for experimentation at that time[7].
Further progression in
research concerning the role of immune system in carcinogenesis led to the
proposal of immunostimulation theory by Prehn (1970) who suggested that the
immune system can actually promote the growth of tumors[10].
Understanding the role of
immune system in tumor rejection and tumor formation led to the modification of
immunosurveillance concept into cancer immunoediting concept that describes the
host protecting and tumor sculpting actions of the immune system in preventing
and also shaping neoplastic disease[7]. Cancer immunoediting
comprises of three phases namely elimination, equilibrium and escape which
encompasses the role of immune system in carcinogenesis[6].
IMMUNOSURVEILLANCE IN CANCER
The primary clinical
data that supported the importance of immunosurveillance as a mechanism of
tumor prevention has been generated by epidemiological studies of
immunodeficient patient populations[11]. Since its conceptualization
by Burnet and Thomas in 1957, several experiments have challenged its validity
based on experimental findings of immunological defects in nude mice. During
the recent years, significant developments have led to the renaissance of this
concept based on certain key findings. An important development is the finding
that endogenously produced interferon γ (IFN- γ) was shown to
protect the host against the growth of transplanted tumors and the formation of
primary chemically induced and spontaneous tumors[12]. Another
important event was the discovery of natural killer (NK) cells and the
possibility of their functioning as effectors of immunosurveillance[7].
The next significant finding was the role of perforin, wherin animal models
lacking perforin were found to be more susceptible to tumor development[13].
These key findings demonstrated that tumor formation is in fact controlled by
host immune system. Various cellular mediators of immunosurveillance were since
being studied and the following section outlines the role of these mediators.
CELLULAR
MEDIATORS OF IMMUNOSURVEILLANCE
The interferon
family was originally recognized for its capacity to protect naive cells
against viral infection and later was seen to have obligate roles in the
elimination phase of cancer immunoediting[14]. The action of IFN- γ in tumor rejection has been explained by different
pathways. Foremost to this is the finding that the tumor cell itself is an important
target in tumor rejection. Experimental findings have concluded that tumor cell
is a physiologically relevant target of IFN- γ in the tumor rejection process[15,16,17]. IFN- γ is also known to enhance tumor cell immunogenecity by
upregulating components of the MHC class I antigen processing and presentation
pathway which can cause tumor rejection[18]. IFN- γ is known to have profound anti-proliferative and/or
pro-apoptotic effect on certain tumor cells[6]. Recent work suggests
that γδ T-cells are an
important source of IFN-γ during the
development of protective anti-tumor response[19]. It was also found
that host cells are important targets of IFN- γ during the development of protective anti-tumor immune
response. Studies have shown that IFN- γ in combination with granulocyte monocyte-colony stimulating factor
(GM-CSF) controls chronic infection thus reducing tumor development[20].
Another possible mechanism is that IFN- γ can induce angiostatic effects in tumors by targeting non-transformed
host cells that are in close proximity to the tumor[21]. Other cells
which have a role in tumor immunosurveillance include macrophages and dendritic
cells, natural killer cells, B-lymphocytes and T-lymphocytes. Dendritic cells
function by upregulating MHC class I and class II molecules on recognition of
pro-inflammatory proteins elaborated by tumors and also upregulate CD80, CD86
and CD 137[22]. Macrophages are efficient phagocytic cells which
have immunosurveillance ability as well as promote tumor growth. Macrophages
operate to both directly destroy tumors and augment the functions of natural
killer cells and T-cells[11]. Natural killer cells represent
cellular populations of the innate immune compartment that protects the host
from tumor formation. Robust infiltration of NK cells is nearly always
associated with a favorable prognosis[23].
CANCER IMMUNOEDITING
Experimental
evidence suggests a dual role of immune system as host protecting as well as
tumor sculpting effects on developing tumors. This led to the discontinuation
of the term cancer immunosurveillance and replaced by the term cancer
immunoediting proposed by Dunn et al (2004)[6] to
appropriately emphasize the dual role of host immune system in preventing and
also shaping neoplastic disease. The process of cancer immunoediting has been
explained based on three phases namely elimination, equilibrium and escape.
The elimination phase
represents the original concept of immunosurveillance. Immunological rejection
of a developing tumor requires an integrated response involving innate and
adaptive immunity[6]. Structures on the transformed cells are
recognized by NK cells, γδ T cells, IL-23,
which are then stimulated to produce IFN-γ that is critical for progression of anti-tumor immune response[24].
Further process involves limited tumor death produced by anti-proliferative and
apoptotic mechanisms activated by IFN-γ killing of tumor cells by mechanisms involving tumor necrosis factor-
related apoptosis ligand (TRAIL), perforin and reactive O2 and N2
intermediates and finally complete elimination of remaining antigen bearing
tumor cells by cytotoxic T-lymphocytes.
In the equilibrium phase,
which is the longest, the host immune system and any tumor cell variant that
has survived the elimination phase enters into a state of dynamic equilibrium. In
this phase, the lymphocytes and IFN-γ exert potent and relentless selection pressure on the tumor bed that
possesses many genetically unstable and mutating tumor cells.
The final escape phase is
characterized by survival of tumor cell variants that have acquired
insensitivity to immunological detection and /or elimination and thus begin to
expand in an uncontrolled manner. Tumor cells dysregulate immune system by
various local and systemic mechanisms. The local mechanism includes prevention
of immune recognition by decreased tumor antigenecity, selectively attracting
tumor promoting agents and rejecting anti-tumor agents, alteration in T-cell
signaling, tryptophan metabolism and proteoglycans. The systemic mechanisms
includes the presence of self-tolerance and regulatory T-cells, changes in
dendritic cell function, myeloid derived suppressor cells, cytokines and
vascular growth factors[11].
ROLE OF IMMUNOLOGICAL CELLS IN ORAL CARCINOGENESIS
The role of immunological
cells such as tumor necrosis factor related apoptosis inducing ligand (TRAIL),
NK cells, dendritic cells, macrophages, eosinophils and mast cells were studied
in oral cancer with an aim to understand its role in tumor progression. Oral
squamous cell carcinoma (OSCC) is a multistep malignancy caused primarily by
tobacco. The progression of OSCC is dependent on tumor cells themselves, the
stromal microenvironment and its components. Evidence indicates that modulation
of stromal cells in tumor microenvironment has a significant bearing on tumor
progression. The stromal cells that were commonly studied are mast cells,
macrophages, eosinophils and angiogenic factors. This section compiles the
various literature data pertaining to these cells.
TRAIL is a type II
transmembrane protein which plays an important role in immunosurveillance
against tumor progression by selectively inducing apoptosis in tumor cells and
not in normal cells[25]. The loss of TRAIL in oral pre-malignancies
and OSCC is being associated with poorer prognosis and tumor progression. Significantly
high levels of TRAIL were found in normal oral mucosa than in oral
pre-malignancies and OSCC[26]. The study concluded that the loss of
TRAIL expression is an early event during oral carcinogenesis and may be
involved in dysregulation of apoptosis and contribute to molecular
carcinogenesis of OSCC.
Mast cells display a diversity of
roles in extracellular matrix degradation, angiogenesis, and innate and
adaptive immune responses due to their ability to release specific products
such as chymase, basic fibroblast growth factors, interleukins, TNF-α and chemokines[27].
Local depletion of resident mast cells and a failure in mast cell migration was
observed in a study by Oliveira- Neto et al (2007)[27] who
concluded that the decrease in mast cells might be related to the failure in
migration and/or local depletion of these cells. The overall impact of
decreased mast cells may reflect an important modification in the
microenvironment during tumorigenesis making it more permissive to epithelial
neoplastic cell proliferation. Ankle et al (2007)[28] showed
increased mast cell count in leukoplakia, oral submucous fibrosis, lichen
planus and OSCC. Various mediators released from the mast cells might be
responsible for the histological changes seen in these lesions. Gomes et al
(2008)[29] in their study showed significant increase in mast cells
density in lip SCC and in dysplastic actinic cheilitis than in normal oral
mucosa. Increase in mast cell count may suggest an immunological cause and the
density may decrease in high grade carcinoma which could be due to an
unfavorable cellular environment. A transition from increase to decrease number
of mast cell in oral mucosa represents a competition between the immunological
system and the tumor cellular environment. Iamaroon et al (2003)[30]
found linear increases in mast cell count from normal oral mucosa,
hyperkeratosis, and epithelial dysplasia to invasive OSCC. They also found a
significant correlation between mast cells and microvascular count in OSCC. These
findings suggest that mast cells may upregulate angiogenesis in OSCC via the
release of mast cell tryptase. The number of mast cells and microvessels may
also be used as indicators for disease progression. Rojas et al (2005)[31]
demonstrated that mast cells were activated and significantly increased in lip
SCC than in normal lip. Significant changes in subpopulations were also found.
Mast cell containing chymase and tryptase was higher at the peritumoral stroma
which plays a role in extracellular matrix degradation and tumor progression at
the invasive front while mast cells tryptase was increased in intratumoral
stroma which may stimulate angiogenesis. Changes in proportion of mast cell
tryptase to mast cell tryptase-chymase could be a useful indicator of
malignancy in lip biopsies.
CD8 cytotoxic T-lymphocytes
are key effectors in the antitumor immunity while CD4 T-cells play a role in
antibody production and activation of CD8 T-cells and macrophages. A study by
Ali et al (2012)[32] did not demonstrate any significant
correlation between CD4, CD8 levels and clinical parameters. Other studies
found a significant correlation between CD4 and CD8 levels with tumor
progression and peritumoral inflammatory infiltrate[33,34,35].
Tumor associated macrophages
are known to play a pro-tumor role in OSCC and tumor progression likely occurs
through activation of the Gas 6/Axl-NF-kB signaling pathway[13]. Li et
al (2002)[37] identified that tumoral accumulation of the
macrophages is associated with stage of tumor invasion. Sica et al
(2006)[38] in their study reported predominance of macrophages in
the peritumoral infiltrate in OSCC. Several studies did not find any
statistical significant difference between infiltrated macrophage and the
pathological stage and grade of OSCC[32,39] (Table 1).
IMMUNOTHERAPY IN HEAD AND NECK CANCER
Development of
immune based cancer therapies is difficult due to the fact that the active
tumor escapes from the host immune system and/or the failure of immune
surveillance to control tumor progression. Thus immune based therapies are
developed to involve multiple components of the body immune system and the drug
trials are based on T-cell immunotherapy, modified autologous tumor cell
vaccine, dendritic cell based vaccine, DNA vaccines, development of monoclonal
antibodies and cytokines[40]. Some of the clinical trials currently
in progress or completed are; multikine which is a leukocyte interleukin
injection developed by CEL-SCI and currently in the stage III trial of head and
neck cancer (www.cel-sci.com); phase II clinical trial of allovectin-7 which is
a experimental gene based immunotherapy (NCT00050388)[41]; effect of
microsphere delivered IL-2, IL-12, GM-CSF in HNSCC conducted by New York
University school of medicine (NCT00899821)[42]; phase I trial of
TLR8 agonist VTX-2337 and cetuximab in treating patients with HNSCC conducted
by University of Washington (NCT01334177)[43]; phase I trial of
vaccine therapy in stage IV HNSCC using recombinant fowlpox-TRICOM vaccine
(NCT00021424)[44]; phase II clinical trial of safety of IRX-2 drug
in head and neck cancer (NCT00210470)[45]; phase I clinical trial of
recombinant interleukin-15 in HNSCC (NCT01727076)[46]; an
interventional study of ADXS 11-001 in HPV induced oro-pharyngeal SCC
(NCT02002182)[47]; phase II clinical trial of neoadjuvant
immunotherapy in OSCC[48] and phase II clinical trial of erlotinib,
an oral epidermal growth factor receptor tyrosine kinase inhibitor in oral
squamous cell carcinoma[49].
CONCLUSIONS
Human immune system
contributes significantly to head and neck carcinogenesis. The concept of
immune system influencing various aspects of human cancer has been studied a
great deal in the past. However its actual role is still debatable as to
whether they promote tumor growth or have tumor inhibiting actions. The
immunosurveillance concept was proposed based on the fact that the body
immunity destroyed tumor cells and prevented the tumor from occurring. Over
time, the concept of immunoediting was given importance which accounted for the
dual role of host immunity in carcinogenesis. Various cellular mediators of
immunity were studied with an attempt to better understand its role in
carcinogenesis. Interferon-γ, mast cells, TNF-α, tumor associated macrophages and eosinophils were evaluated in OSCC
but not much has been proved. A more comprehensive assessment is required to
prove the role of these immune cells in OSCC. This is necessary in view of
implementing immunotherapy as a therapeutic measure in the treatment of
OSCC.
CONFLICT
OF INTERESTS
There are no
conflicts of interest with regard to the present study.
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Peer reviewers: Ho-Sheng Lin, MD, FACS,
Professor, Department of Otolaryngology-Head and Neck Surgery, Wayne State
University School of Medicine and Karmanos Cancer Institute, Chief, Section of
Otolaryngology, Department of Surgery, John D. Dingell VA Medical Center, 4201
St. Antoine, 5 E University Health Center, Detroit, MI 48201, the United
States; Pablo Varela-Centelles, Departamento de Estomatología. Facultad de
Medicina y Odontología, Universidad de Santiago de Compostela, Entrerríos s/n,
15782 Santiago de Compostela. A Coruña. Spain; Drago B. Jelovac, MSci, DMD,
MSIII, Clinic for Maxillofacial surgery, School of dental medicine, dr Suboticaća
4, 11000, Serbia.
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