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25 Host Defences Against Cancer
Cancer initiation Elimination
Tumour progression
malignant
Equilibrium Escape
430
Nevertheless, some may argue that this theory is overly simplistic and fails to account for the
complexity of cancer development. Additionally, recent research has suggested that the immune
system may aid the growth of tumours, rather than actively fighting them(1, 5). Overall, the
immune surveillance theory can help us understand how the immune system functions and how
it may play a role in cancer development. However, it is essential to recognise that the immune
system is much more complex than initially thought.
In this context, cancer immunoediting encompasses three distinct phases of tumour progression: elimination, equilibrium and escape (Figure25.1)(4–6). During the elimination phase, the
immune system actively recognises and eliminates the tumour by immune cells such as natural
killer (NK) and cytotoxic T cells. The equilibrium phase is when the immune response is not able
to eliminate the tumour. So on, it might stimulate the tumour instead by inducing tumour cells to
acquire a more aggressive phenotype, leading to a disease’s progress. In the final phase, escape or
immunosuppression, the tumour can evade the immune system by releasing suppressive cytokines,
mediating the recruitment of immunosuppressive cell populations as regulatory T cells (Tregs)
and myeloid- derived suppressor cells (MDSC), and inducing T- cell exhaustion(7, 8). The result is
a less immunogenic tumour and more capable of establishing an immunosuppressive microenvironment(6). Based on this last concept, tumour cells’ co- option and subversion of the immune
system is a process in which tumour cells adapt to the presence of tumour- infiltrating immune
cells and use them to their advantage. This process helps tumour cells avoid immune recognition
and destruction, allowing them to survive and grow in the presence of immune cells. Tumour
Non-
cells
Cancer
cell
T lymphocytes
Natural killer cells
Macrophages
Neutrophils
Figure25.1 Cancer immunoediting involves three key phases. Elimination corresponds to the concept of
immunosurveillance, and the immune system actively seeks and destroys early tumour cells to prevent their
growth. Equilibrium represents the stage in which the immune system continually assesses and influences
the evolution of tumour cells, favouring those with increased resistance to immune attacks. Escape is the
phase when the tumour, sculpted by the immune system’s pressure, starts to grow uncontrollably within an
immunocompetent host, evading immune responses.
Suppression of
transformed cells
N∅
CD8+
T cell
Dendritic cells
Regulatory T cells
MDSC
Tumour antigens
Tumour dormancy
Selective immune pressure
NK
M
∅
NK
M1
N1
DC
Inhibit
Induce/Transforme
Naive
T cell
M2
N2
Treg
CD4+
T cell
CD8+
T cell
MDSC
NK
t.me/Dr_Mouayyad_AlbtousH
25.3 Tumour Antigens
cellscan use various strategies to capture and subvert the immune system, such as releasing
immunomodulatory molecules, producing cytokines and chemokines that attract and activate
immune cells and manipulating cell–cell interactions(1, 9, 10).
25.3 Tumour Antigens
Tumours comprise cells with altered genetic material, which sets them apart from the surrounding
normal tissue, expressing proteins or antigens that the immune system can recognise as foreign.
The immune system then mounts a specific response, which can be effective in controlling tumour
growth(11). This is the basis for immunotherapy strategies that rely on tumour antigen identification. In this sense, cancer antigens can be classified into viral antigens, mutated antigens/tumourspecific antigens (TSA) and unmutated antigens/tumour- associated antigens (TAAs)(12, 13). The
immune system’s complex relationship with these tumour antigens in head and neck cancer. In
some cases, these antigens can trigger an immune response against the tumour, leading to tumour
cell destruction. However, tumours often develop mechanisms to evade the immune system, such
as upregulating immune checkpoint molecules like programmed death- ligand 1 (PD- L1) (7, 8).
Immunotherapies that target these interactions aim to overcome these evasion strategies and
enhance the immune system’s ability to recognise and destroy cancer cells. Ongoing research seeks
to identify more specific tumour antigens and develop personalised immunotherapies for head
and neck cancer patients. A brief description of some examples of cancer antigens related to head
and neck cancer is described in Table25.1.
431
25.3.1 Viral Antigens
Viral antigens related to head and neck cancer are primarily associated with human papillomavirus (HPV) and Epstein–Barr virus (EBV). These viruses can contribute to the development of head
and neck cancer. However, it is worth noting that not all cases of head and neck cancer are caused
by viral infections, but in those cases where viruses are implicated, these viral antigens can be
important markers(12, 13).
25.3.2 Tumour- specific Antigens
TSAs related to head and neck cancer are antigens unique to the tumour cells and not found in
normal, healthy tissues. These antigens are specific to the cancer and serve as ideal targets for
immunotherapy and diagnostics. TSAs can result from genetic mutations or other alterations in
the tumour cells. Head and neck cancers can express various TSAs that are recognised by the
immune system. These antigens are crucial in interacting with cancer cells and the immune
system(11).
25.3.3 Tumour- associated Antigens
TAAs related to head and neck cancer are antigens expressed in both tumour and normal, healthy
cells but are overexpressed or abnormally expressed in the tumour. TAAs are not as specific to
cancer as TSAs, but they can still be used as targets for immunotherapy and diagnostics in head
and neck cancer(11).
t.me/Dr_Mouayyad_AlbtousH
25 Host Defences Against Cancer
432
Table25.1 Overview ofsome cancer antigens related tohead andneck cancer.
Antigen Markers Application overview
Viral antigen HPV The viral oncoproteins E6 and E7 are key antigens in this context. These
oncoproteins can interfere with the regulation of cell growth and
contribute to the development of cancer. They are often targeted for
diagnostic and therapeutic purposes(13, 14).
EBV It can be associated with various types of head and neck cancers,
including nasopharyngeal carcinoma. Several EBV antigens are relevant,
including EBNA1 (Epstein–Barr nuclear antigen 1), LMP1 (latent
membrane protein 1) and LMP2. These antigens can trigger an immune
response and may serve as targets for immunotherapy or diagnostic
tests(13, 14).
TSA TP53 TP53mutations are a common genetic alteration in head and neck cancer
and are associated with more aggressive disease. These mutations can also
influence the immune response to cancer, potentially creating an
immunosuppressive microenvironment. The interplay between TP53 and
the immune system has important implications for treatment strategies,
including the use of immunotherapies(13).
Neoantigens Neoantigens are the most well- known TSAs, and they result from genetic
mutations that create novel protein sequences not present in normal cells.
These mutations can occur in genes associated with cell growth,
proliferation and survival. Neoantigens are highly specific to the
individual’s tumour and can be targeted by the immune system or used to
design personalised cancer vaccines(15).
TAA MAGE These antigens are a family of TAAs that can be found in various cancer
types, including some head and neck cancers. They are targets for
immunotherapies like cancer vaccines and adoptive T- cell therapies(16).
EGFR It is a cell surface receptor that plays a role in cell growth and
proliferation. In many head and neck cancers, EGFR is overexpressed,
leading to increased signalling and cell growth. Targeting EGFR with
monoclonal antibodies like cetuximab is a common strategy in head and
neck cancer treatment(13).
CEA It is a glycoprotein that is often found at higher levels in some head and
neck cancers. It is used as a biomarker for disease progression and can be
targeted in immunotherapies(16).
ALDH Some preclinical and clinical studies have investigated the use of ALDH
inhibitors in combination with immunotherapies to enhance the immune
response against head and neck cancer. These therapies aim to sensitise
the tumour to immune- mediated destruction(17).
IDO It is an enzyme that plays a role in the regulation of the immune system,
and it has relevance in head and neck cancer due to its involvement in
immune evasion and tumour progression. Researchers have explored IDO
inhibitors as potential immunotherapeutic agents. IDO inhibitors, often
used in combination with checkpoint inhibitors like anti- PD- 1 or
anti- CTLA- 4 antibodies, aim to restore the anti- tumour immune response
by blocking the immunosuppressive effects of IDO(18).
TSA = tumour- specific antigen, TAA = tumour- associated antigen, HPV = human papillomavirus,
EBV = Epstein–Barr virus, MAGE = melanoma- associated antigen, EGFR = epithelial growth factor receptor,
CEA = carcinoembryonic antigen, ALDH = aldehyde dehydrogenase, IDO = indoleamine 2,3-dioxygenase.
t.me/Dr_Mouayyad_AlbtousH
25.4 Cellular Immunity
25.4 Cellular Immunity
433
Immune cells in the TME can be divided into two types: tumour- antagonising and tumour-
+
promoting(19). Tumour- antagonising cell types include CD8
cytotoxic T cells, effector CD4+
Tcells, NK cells, dendritic cells (DCs), M1- polarised macrophages and N1- polarised neutrophils.
Tumour- promoting immune cells consist of Treg and MDSCs, which can be further subdivided
into two subtypes: the polymorphonuclear MDSCs and the monocytic MDSCs. The role of B cells
in TME is not clear, with them potentially having both tumour- antagonising and tumour- promoting
+
roles. In the initial phase of tumour progression, NK cells and CD8
T cells act as cytotoxic agents
to recognise and eradicate tumour cells. However, some less immunogenic tumour cells can evade
immune surveillance, allowing them to become dominant and eventually set up an immunosuppressive microenvironment that weakens the tumouricidal effects(20–22). In this chapter, a greater
focus is placed on tumour- antagonising immune cells, highlighting their role in host defences
against cancer.
25.4.1 Macrophages
Macrophages are mononuclear phagocytes that play an important role in the body’s first defence
against cancer, recognising cancer cells and initiating an immune response. The activation of macrophages is determined by the type and level of the cytokines, pathogen- associated molecular patterns, metabolic signals, cell–cell interactions and tissue- specific signals that a cell receives from
its environment. The classically activated M1macrophages are pro- inflammatory and kill tumour
cells as inducible and effector cells in the T- helper type 1 immune response. M1macrophages are
typically activated by T- helper type 1 cytokines, including interferon- γ (IFN- γ), tumour necrosis
factor- α (TNF- α) or bacterial lipopolysaccharide (LPS). These macrophages produce proinflamma-
tory cytokines, such as IL- 1β, IL- 2, IL- 6, IL- 12, IL- 23 and TNF- α, and chemokines including CCL5,
CXCL9, CXCL10 and CXCL5(23).
M2macrophages, also called alternative macrophages, are anti- inflammatory and can be found
promoting cell growth and repair. Tumour- associated macrophages (TAM) are characterised by an
immunosuppressive M2- like phenotype(24). The M2 phenotype is induced by various Th cytokines
(IL- 4, IL- 10 and IL- 13) and is characterised by increased secretion of anti- inflammatory cytokines,
such as IL- 10 and tissue growth factor- β (TGF- β). Therefore, the state and polarisation of mac-
rophages in the body can be critical. In this context, recent studies have shown that potentially
malignant conditions that have reduced rates of malignant transformation, such as oral lichen
planus, have an M1macrophage profile(25). Another study demonstrated that polarisation of
M2macrophages in oral leucoplakia was significantly higher in lesions that underwent malignant
transformation in the five- year follow- up compared to lesions that did not undergo malignant
transformation in this period(26).
25.4.2 Dendritic Cells
The critical role of DCs in orchestrating the development of protective immune responses is particularly relevant in cancer. First, the presence of certain TAA presented by DCs is necessary for a
strong and coordinated T- cell response against TSA. Second, DCs are essential for modulating
tumour- associated immunosuppression, which often surrounds the TME. Finally, the activation
and maturation status of DCs can shift the balance between inducing a self- tolerant or an autoimmune host response. DCs can form the interface between the host’s innate and adaptive immune
t.me/Dr_Mouayyad_AlbtousH
25 Host Defences Against Cancer
434
systems to enable efficient anti- tumour immunity. Depending on the location and activation state,
distinct DC subsets are classified as conventional DC type 1 (cDC1) and type 2 (cDC2), monocytederived DC (MoDC), plasmacytoid DC (pDC) and DC3(27).
In summary, DCs play a critical role in host defences against cancer by serving as antigenpresenting cells that capture and process antigens from the TME, migrate to the tumour- associated
draining lymph node and prime naïve T- cells to mount an effective anti- tumour response(28). DCs
also coordinate actions involving the recruitment of T- cells into the TME, the production of chemotactic gradients, and the in situ interaction with effector T- cells and local cytokine production(29).
Thus, DCs are essential for mounting a successful anti- tumour response, and the quality of their
initial priming event is likely critical for long- term protective immunity against cancer.
25.4.3 Neutrophils
Neutrophils are the most common type of leukocyte in our circulation and have several roles in the
immune system. They are involved in the first line of defence against pathogens, can act as phagocytic cells and can be applied in T- cell activation and forming neutrophil extracellular traps (NETs)
to fight infections and promote thrombosis(30, 31). The expression of markers such as CD11b,
CD14, CD15, CD16, CD62L and CD66b can help to identify these cells(31, 32).
The contribution of tumour- associated neutrophils (TANs) to cancer progression remains uncertain since they can have both pro- and anti- tumour properties. This polarisation of the neutrophil
population into N1 and N2 phenotypes has been observed, N1 being the cytotoxic phenotype and
N2 being pro- tumour with increased expression of angiogenesis and invasion- promoting factors
such as CXCR4, VEGF and MMP- 9. Furthermore, neutrophils can revert to the cytotoxic N1
phenotype in the presence of IFN- β(30, 31).
25.4.4 Natural Killer Cells
NK cells are a powerful and versatile component of the innate immune system, with the ability to
recognise and eliminate cancer cells without prior antigen exposure. They are regulated by several
activating and inactivating receptors, which can be exploited by cancer cells to reduce their cytotoxic activity. They are capable of distinguishing tumour cells from healthy ones and possess cyto-
+
toxic abilities like those of CD8
NK cells can be identified by their surface markers, such as CD3
T cells(33).
−
CD56+ and NKp46(34). They
largely depend on cytokines, especially IL- 2 and IL- 15, and transcription factors, such as Nfil3, Id2,
Tox, EOMES and T- bet, for development and maturation(35). In the clinic, the prognostic role of
NK cells in tumour- bearing patients is vigorously discussed. Before treatment, increased circulat-
−
ing NK cells or CD3
CD56+ cells may be related to better outcomes in many tumour types such as
myeloma, Hodgkin’s lymphoma, lung cancer and colorectal cancer(33).
−
Studies on bladder cancer primary tumours have demonstrated that high levels of CD3
CD56+
NK cells are associated with significantly improved overall survival(36). In contrast, increased NK
cells impede anti- tumour responses in diffuse large B- cell lymphoma, where higher infiltration of
NK cells is correlated with unfavourable clinical outcomes despite an initial improved complete
response(33). The complexity and heterogeneity of NK cells display a synergistic effect with other
immune cells in some instances, whereas it leads to a decreased anti- tumour response in others. In
+
summary, NK cells and CD8
but share many similarities. Combination immunotherapy utilising both NK cells and CD8
T cells have different functions in immune surveillance and response
+
T cells
can constitute a promising future strategy for tackling tumour immune escape(37).
t.me/Dr_Mouayyad_AlbtousH
25.4 Cellular Immunity
25.4.5 CD8+ Cytotoxic T Cells
CD8+ cytotoxic T lymphocytes (CTLs) are a significant part of the adaptive immune system and
are essential in controlling intracellular pathogens. Effector CTL can induce apoptotic death in
specific cells, with simultaneous use of granules (perforin, granzyme, cathepsin C and granulysin) and receptors (Fas and tumour necrosis factor) pathways(38). Although NK cells also promote cell destruction, CTLs differ in that they have a precise specificity for major histocompatibility
complex (MHC) class I molecules. This makes CTL ideal for anti- tumour immunisation due to
their responsiveness and broad expression of MHC class I molecules, aptitude for travelling
through the body, and sensitive recognition of MHC class I complexes. Additionally, CTL can
work through non- lethal means, such as by producing IFN- γ, which has tumour- preventing
qualities(39).
+
For effective CTL activation, naïve CD8
CTL priming is achieved when the DCs are activated, usually when they link with CD4
T cells require triggering by antigen from DC. Optimal
+
helper T
cells (Th cells) to present the antigen on MHC class II. Furthermore, antigen should be processed
by the DC, with it being presentable through MHC class I and II, while appropriate costimulatory
signals are presented to the TCR(40).
Immunotherapy today primarily focuses on T lymphocytes, mainly restoring exhausted CD8
CTLs. A demonstration of this type of strategy is the blocking of receptors/ligands that hamper the
activation of CTLs, including programmed cell death protein 1 (PD- 1), its primary ligand PD- L1,
cytotoxic T- lymphocyte antigen 4 and lymphocyte- activation gene- 3with the application of monoclonal antibodies that neutralise them(39).
435
+
25.4.6 Effector CD4+ T Cells
The importance of Th cells, also called CD4+ T cells, in orchestrating anti- tumour responses was
+
initially overlooked as the successes of CD8
T cell- based immunotherapies had become the pri-
mary focus. However, more reports in the last 5 years have clarified their vital role. It has been
+
demonstrated that mutant neoepitopes recognised by CD4
+
nomas(41), promoting mainly a CD4
, rather than CD8+ T- cell response(42). Afterwards, another
T cells were present in human mela-
group observed that personalised neoantigen vaccines for melanoma patients significantly acti-
+
vated CD4
such CD4
, not CD8+ T cells(43, 44). Moreover, preclinical mouse models have demonstrated that
+
subset Th1- like T cells grant a protective benefit when transferred to non- tumour hosts
and are present in the peripheral blood of melanoma patients who have received recombinant
immunotherapy(45).
+
Th cells also play an essential role in reinforcing the anti- tumour CD8+ response as they
CD4
can acquire cytotoxicity against melanoma(40, 46, 47). In this context, studies have shown correla-
+
tions between improved prognosis and the levels of anti- tumour CD4
T cells in colorectal,
oxaliplatin- treated and non- small cell lung cancer patients, respectively(7, 8, 48). These clinical
+
and preclinical studies demonstrate that CD4
T cells are integral in driving enduring and success-
ful immune responses.
25.4.7 Natural Killer T Cells
Natural killer T (NKT) cells belong to the group of innate- like T lymphocytes and play a critical
role in the innate and adaptive immune systems by bridging the two. They possess characteristics
of both T and NK cells, carrying a rearranged T- cell receptor with receptors such as CD56, CD161,
t.me/Dr_Mouayyad_AlbtousH
25 Host Defences Against Cancer
436
NKp46, CD94, CD16 and killer- cell immunoglobulin- like receptors(33, 34, 49). NKT cells can have
both immunosuppressive and immunostimulatory roles in various settings, and their activity is
dependent on the current state of the immune system and the type of disease. NKT cells can shape
the adaptive immune response in various ways, either by acting as antigen- presenting cells to conventional T cells or by producing cytokines to direct other cells in the immune system, such as B
cells, CTLs and NK cells(49).
NKT cells can bind to cancer antigen- MHC complexes on the surface of cancer cells and then
recognise and kill the cancer cells by secreting various cytokines and effector molecules. NKT cells
can also activate and cooperate with tumour- specific CTLs through the secretion of cytokines. In
addition, NKT cells can undermine the effects of immunosuppressive factors, such as IL- 10 and
TGF- β, present in the TME. Therefore, the presence of NKT cells in the TME has been correlated
with better patient outcomes, which is why NKT cells have been proposed as a potential therapeutic target for cancer immunotherapy(50).
25.5 Humoral Immunity
Humoral immunity is less effective at controlling tumour growth than CTL immunity. Nevertheless,
antibodies against tumour antigens found in cancer patients’ serum have been examined in various studies. The correlation between this humoral immune response and biological or clinical
outcome has not been fully explored. Some antibodies may be markers of exposure to the antigen
without serving any function. It is possible these responses can be used for early detection, prognosis and post- treatment surveillance; however, there is still little data on antibody pre- diagnostic
values(51). Future investigation should focus on dynamic antibody levels during disease, therapy
response and survival.
25.6 Conclusions
In summary, the human body has several natural defence mechanisms to protect against the development and progression of cancer. These host defences are crucial in preventing the growth of
cancer cells and maintaining overall health. Immune cells can identify abnormal proteins or antigens on the surface of cancer cells, initiating an immune response to target and destroy them. It is
important to note that while these host defences are crucial in preventing cancer, they are not
always foolproof. Genetic factors, environmental exposures and other risk factors can increase the
likelihood of cancer development. Additionally, advances in medical research have led to the
development of various new cancer treatments, including immunotherapies that combat cancer
when it does occur.
Acknowledgements
This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível
Superior– Brasil (CAPES) and Andreia Bufalino received funding for this research from the São
Paulo Research Foundation (FAPESP) (grant #2022/14672- 0).
t.me/Dr_Mouayyad_AlbtousH
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