best slide to understand role of immune response to fight tumor/cancer cell

1. Immunity to Tumors

2. • Cancer is a major health problem worldwide and one of the most
important causes of morbidity and mortality in children and adults.
• Cancers arise from the uncontrolled proliferation and spread of
clones of malignantly transformed cells.
• The lethality of malignant tumors is determined in large part by their
unregulated proliferative activity, the resistance of tumor cells to
apoptotic death, and the ability of tumor cells to invade host tissues
and metastasize to distant sites.
• The possibility that cancers can be eradicated by specific immune
responses has been the impetus for a large body of work in the field
of tumor immunology

3. • The concept of immune surveillance, which was proposed by Macfarlane
Burnet in the 1950s, states that a physiologic function of the immune
system is to recognize and destroy clones of transformed cells before they
grow into tumors and to kill tumors after they are formed.
• The existence of immune surveillance has been demonstrated by the
increased incidence of some types of tumors in immunocompromised
experimental animals and humans.
• Although the overall importance of immune surveillance has been
controversial, it is now clear that the innate and adaptive immune systems
do react against many tumors, and exploiting these reactions to specifically
destroy tumors remains an important goal of tumor immunologists.

4. GENERAL FEATURES OF TUMOR IMMUNITY
• Several characteristics of tumor antigens and immune responses to
tumors are fundamental to an understanding of tumor immunity and
for the development of strategies for cancer immunotherapy.

5. Tumors stimulate specific, adaptive immune
responses.
• Clinical observations and animal experiments have established that
although tumor cells are derived from host cells, the tumors elicit
immune responses.
• Histopathologic studies show that many tumors are surrounded by
mononuclear cell infiltrates composed of T lymphocytes, natural killer
(NK) cells, and macrophages, and that activated lymphocytes and
macrophages are present in lymph nodes draining the sites of tumor
growth

6. • The first experimental demonstration that tumors can induce protective
immune responses came from studies of transplanted tumors performed in
the 1950s.
• A sarcoma may be induced in an inbred mouse by painting its skin with the
chemical carcinogen methylcholanthrene (MCA).
• If the MCA-induced tumor is excised and transplanted into other syngeneic
mice, the tumor grows.
• In contrast, if the tumor is transplanted back into the original host, the
mouse rejects the tumor.
• The same mouse that had become immune to its tumor is incapable of
rejecting MCA-induced tumors produced in other mice.

7. • Furthermore, T cells from the tumor-bearing animal can transfer
protective immunity to the tumor to another tumor-free animal.
• Thus, immune responses to tumors exhibit the defining
characteristics of adaptive immunity, namely, specificity, memory,
and the key role of lymphocytes.
• As predicted from these transplantation experiments, the most
effective response against naturally arising tumors appears to be
mediated mainly by T lymphocytes.

9. Immune responses frequently fail to prevent the growth
of tumors
• There may be several reasons that antitumor immunity is unable to
eradicate transformed cells.
• First, tumor cells are derived from host cells and resemble normal cells in
many respects.
• Therefore, most tumors tend to be weakly immunogenic.
• Tumors that elicit strong immune responses include those induced by
oncogenic viruses, in which the viral proteins are foreign antigens.
• Second, the rapid growth and spread of tumors may overwhelm the
capacity of the immune system to effectively control a tumor, which
requires that all the malignant cells be eliminated.
• Third, many tumors have specialized mechanisms for evading host immune
res

10. TUMOR ANTIGENS
• A variety of tumor antigens that may be recognized by T and B lymphocytes
have been identified in human and animal cancers.
• In the experimental situation, as in MCA-induced mouse sarcomas, it is
often possible to demonstrate that these antigens elicit adaptive immune
responses and are the targets of such responses.
• Antigens that are expressed on tumor cells but not on normal cells are
called tumor-specific antigens; some of these antigens are unique to
individual tumors, whereas others are shared among tumors of the same
type.
• Tumor antigens that are also expressed on normal cells are called tumor
associated antigens; in most cases, these antigens are normal cellular
constituents whose expression is aberrant or dysregulated in tumors.

12. IMMUNE RESPONSES TO TUMORS
• The effector mechanisms of both innate and adaptive immunity have
been shown to kill tumor cells
• Innate Immune Responses to Tumors
• Some of the early research on functions of effector cells of the innate
immune system, including NK cells and macrophages, focused on the
ability of these cells to kill cultured tumor cells.

13. NK Cells
• NK cells kill many types of tumor cells, especially cells that have
reduced class I MHC expression and express ligands for NK cell
activating receptors.
• In vitro, NK cells can kill virally infected cells and certain tumor cell
lines, especially hematopoietic tumors.
• NK cells also respond to the absence of class I MHC molecules
because the recognition of class I MHC molecules delivers inhibitory
signals to NK cells

14. Macrophages
• Macrophages are capable of both inhibiting and promoting the growth and
spread of cancers, depending on their activation state.
• Classically activated M1 macrophages, display various anti-tumor
functions.
• These cells can kill many tumor cells more efficiently than they can kill
normal cells
• Possible mechanisms include direct recognition of some surface antigens of
tumor cells and activation of macrophages by IFN-γ produced by tumor-
specific T cells.
• M1 macrophages can kill tumor cells by several mechanisms, probably the
same as the mechanisms of macrophage killing of infectious organisms.
• These include the release of lysosomal enzymes, reactive oxygen species,
and nitric oxide.

15. • M1 macrophages also produce the cytokine tumor necrosis factor
(TNF), which was first characterized, as its name implies, as an agent
that can kill tumors.
• We now know it does so mainly by inducing thrombosis in tumor
blood vessels.
• In contrast, M2 macrophages may contribute to tumor progression.
• These cells secrete vascular endothelial growth factor (VEGF),
transforming growth factor-β (TGF-β), and other soluble factors that
promote tumor angiogenesis.

16. Adaptive Immune Responses to Tumors
• Tumors elicit both T cell–mediated and humoral immune responses.
• T cells are the principal mediators of antitumor immunity, and this
realization has led to considerable efforts to enhance T cell responses
for the immunotherapy of cancers

17. T Lymphocytes
• The principal mechanism of adaptive tumor immunity is killing of
tumor cells by CD8+ CTLs.
• The ability of CTLs to provide effective anti-tumor immunity in vivo is
most clearly seen in animal experiments using carcinogen induced
and DNA virus–induced tumors.
• CTLs may perform a surveillance function by recognizing and killing
potentially malignant cells that express peptides that are derived
from tumor antigens and are presented in association with class I
MHC molecules

19. • The importance of CD4+ helper T cells in tumor immunity is less clear.
• CD4+ cells may play a role in anti-tumor immune responses by providing
cytokines for effective CTL development.
• In addition, helper T cells specific for tumor antigens may secrete
cytokines, such as TNF and IFN-γ, that can increase tumor cell class I MHC
expression and sensitivity to lysis by CTLs.
• IFN-γ may also activate macrophages to kill tumor cells.
• The importance of IFN-γ in tumor immunity is demonstrated by the finding
of increased incidence of tumors in knockout mice lacking this cytokine,
the IFN-γ receptor, or components of the IFN-γ receptor signaling cascade.

20. Antibodies
• Tumor-bearing hosts may produce antibodies against various tumor antigens.
• For example, patients with EBV associated lymphomas have serum antibodies
against EBV-encoded antigens expressed on the surface of the lymphoma cells.
• Antibodies may kill tumor cells by activating complement or by antibody-
dependent cell mediated cytotoxicity, in which Fc receptor–bearing macrophages
or NK cells mediate the killing.
• However, the ability of antibodies to eliminate tumor cells has been
demonstrated largely in vitro, and there is little evidence for effective humoral
immune responses against tumors.
• Some effective therapeutic anti-tumor antibodies that are passively administered
to patients likely work by antibody-dependent cell mediated cytotoxicity.

21. EVASION OF IMMUNE RESPONSES BY TUMORS
• Many cancers develop mechanisms that allow them to evade anti-
tumor immune responses.
• These mechanisms can broadly be divided into those that are
intrinsic to the tumor cells and those that are mediated by other
cells
• A major focus of tumor immunology is to understand the immune
evasion mechanisms of tumors, with the hope that interventions to
prevent immune evasion will increase the immunogenicity of tumors
and maximize the responses of the host

22. Intrinsic Mechanisms of Immune Evasion by Tumor Cells
• Several properties of tumor cells enable them to escape host defenses.
• Tumors may lose expression of antigens that elicit immune responses.
• Such “antigen loss variants” are common in rapidly growing tumors and
can readily be induced in tumor cell lines by culture with tumor specific
antibodies or CTLs.
• Given the high mitotic rate of tumor cells and their genetic instability,
mutations or deletions in genes encoding tumor antigens are common.
• If these antigens are not required for growth of the tumors or
maintenance of the transformed phenotype, the antigen-negative tumor
cells have a growth advantage in the host.
• Analysis of tumors that are serially transplanted from one animal to
another has shown that the loss of antigens recognized by tumor-specific
CTLs correlates with increased growth and metastatic potential.

23. • Apart from tumor-specific antigens, class I MHC expression may be
downregulated on tumor cells so that they cannot be recognized by
CTLs.
• Various tumors show decreased synthesis of class I MHC molecules,
β2-microglobulin, or components of the antigen-processing
machinery, including the transporter associated with antigen
processing and some subunits of the proteasome.
• These mechanisms are presumably adaptations of the tumors that
arise in response to the selection pressures of host immunity, and
they may allow tumor cells to evade T cell– mediated immune
responses.

24. • Tumor antigens may be inaccessible to the immune system.
• The cell surface antigens of tumors may be hidden from the immune
system by glycocalyx molecules, such as sialic acid–containing
mucopolysaccharides.
• This process is called antigen masking and may be a consequence of
the fact that tumor cells often express more of these glycocalyx
molecules than normal cells do.

25. • Tumors may fail to induce strong effector T cell responses because most
tumor cells do not express costimulators or class II MHC molecule.
• Costimulators are required for initiation of T cell responses, and class II
molecules are needed for the activation of helper T cells, which in some
circumstances are required for the differentiation of CTLs.
• Therefore, the induction of tumor-specific T cell responses often requires
cross-priming by dendritic cells, which do express costimulators and class
II molecules.
• If such APCs do not adequately take up and present tumor antigens and
activate helper T cells, CTLs specific for the tumor cells may not develop.

26. • Tumors may engage molecules that inhibit immune responses.
• There is good experimental evidence that T cell responses to some tumors
are inhibited by the involvement of CTLA-4 or PD-1
• A possible reason for this role of CTLA-4 is that tumor antigens are
presented by APCs in the absence of strong innate immunity and thus with
low levels of B7 costimulators.
• These low levels may be enough to engage the high-affinity receptor CTLA-
4.
• PD-L1, a B7 family protein that binds to the T cell inhibitory receptor PD-1
is expressed on many human tumors, and animal studies indicate that
antitumor T cell responses are compromised by PD-L1 expression

27. • PD-L1 on APCs may also be involved in inhibiting tumor-specific T cell
activation.
• there are ongoing clinical trials of blockade of the CTLA-4 and PD-
L1/PD-1 pathways to enhance tumor immunity.
• Some tumors express Fas ligand (FasL), which recognizes the death
receptor Fas on leukocytes that attempt to attack the tumor;
engagement of Fas by FasL may result in apoptotic death of the
leukocytes.

28. • Secreted products of tumor cells may suppress anti-tumor immune
responses.
• An example of an immunosuppressive tumor product is TGF-β, which
is secreted in large quantities by many tumors and inhibits the
proliferation and effector functions of lymphocytes and macrophage

29. Extrinsic Cellular Suppression of Anti-Tumor Immunity
• Several cell populations have been described in tumor bearing
patients and animals that suppress anti-tumor immunity.

30. • Tumor-associated macrophages may promote tumor growth and
invasiveness by altering the tissue microenvironment and by
suppressing T cell responses.
• These macrophages have an M2 phenotype, and they secrete
mediators, such as IL-10, prostaglandin E2, and arginase, that impair T
cell activation and effector functions.
• Tumor-associated macrophages also secrete factors that promote
angiogenesis, such as TGF-β and VEGF, which enhances tumor
growth.

31. • Regulatory T cells may suppress T cell responses to tumors.
• Evidence from mouse model systems and cancer patients indicates
that the numbers of regulatory T cells are increased in tumor-bearing
individuals, and these cells can be found in the cellular infiltrates in
certain tumors.
• Depletion of regulatory T cells in tumor-bearing mice enhances anti-
tumor immunity and reduces tumor growth.

32. • Myeloid-derived suppressor cells (MDSCs) are immature myeloid
precursors that are recruited from the bone marrow and
accumulate in lymphoid tissues, blood, or tumors of tumor-bearing
animals and cancer patients and suppress anti-tumor innate and T
cell responses

33. IMMUNOTHERAPY FOR TUMORS
• The potential for treatment of cancer patients by immunologic
approaches has held great promise for oncologists and
immunologists for many years.
• The main reason for interest in an immunologic approach is that most
current therapies for cancer rely on drugs that kill dividing cells or
block cell division, and these treatments have severe effects on
normal proliferating cells.
• As a result, the treatment of cancers causes significant morbidity and
mortality

34. • Immune responses to tumors may be specific for tumor antigens
and will not injure most normal cells.
• Therefore, immunotherapy has the potential of being the most
tumor-specific treatment that can be devised.
• Advances in our understanding of the immune system and in defining
antigens on tumor cells have encouraged many new strategies.
• Immunotherapy for tumors aims to augment the weak host immune
response to the tumors (active immunity) or to administer tumor-
specific antibodies or T cells, a form of passive immunity.

35. • Stimulation of Active Host Immune Responses to Tumors
• The earliest attempts to boost anti-tumor immunity relied on
nonspecific immune stimulation.
• More recently, vaccines composed of killed tumor cells, tumor
antigens, or dendritic cells incubated with tumor antigens have been
administered to patients, and strategies to enhance immune
responses against the tumor are being developed.

36. Vaccination with Tumor Antigens
• Immunization of tumor-bearing individuals with tumor antigens may
result in enhanced immune responses against the tumor

40. • Augmentation of Host Immunity to Tumors with Costimulators and
Cytokines
• Cell-mediated immunity to tumors may be enhanced by expressing
costimulators and cytokines in tumor cells and by treating tumor-
bearing individuals with cytokines that stimulate the proliferation and
differentiation of T lymphocytes and NK cells.

42. • Blocking Inhibitory Pathways to Promote Tumor Immunity
• Another immunotherapeutic strategy is based on the idea that tumor cells exploit various normal
pathways of immune regulation or tolerance to evade the host immune response.
• One series of studies in mice and humans has targeted the inhibitory receptor for B7, CTLA-4,
which functions normally to shut off responses against self antigens
• Combination therapy with a tumor vaccine and an antibody that blocks CTLA-4 induces a strong
anti-tumor T-cell response that destroys the tumor.
• Anti–CTLA-4 antibody has been used with some success in clinical trials with patients with
advanced tumors.
• A common complication of this treatment has been the development of autoimmune reactions,
which is predictable in light of the known role of CTLA-4 in maintaining self-tolerance.
• T cell responses against tumors may also be inhibited by the PD-L1/PD-1 pathway.
• Antibody blockade of PD-1 is effective in enhancing T cell killing of tumors in mice, and human
clinical trials using this approach are under way.

43. • Nonspecific Stimulation of the Immune System
• Immune responses to tumors may be stimulated by the local
administration of inflammatory substances or by systemic treatment
with agents that function as polyclonal activators of lymphocytes.
• Nonspecific immune stimulation of patients with tumors by injection
of inflammatory substances such as bacillus CalmetteGuérin (BCG) at
the sites of tumor growth has been tried for many years.

44. • Passive Immunotherapy for Tumors with T Cells and Antibodies
• Passive immunotherapy involves the transfer of immune effectors,
including tumor-specific T cells and antibodies, into patients.
• Passive immunization against tumors is rapid but does not lead to
long-lived immunity.
• Some anti-tumor antibodies are now approved for the treatment of
certain cancers.

45. • Adoptive Cellular Therapy
• Adoptive cellular immunotherapy is the transfer of cultured immune
cells that have anti-tumor reactivity into a tumor-bearing host.
• The cells to be transferred are expanded from the lymphocytes of
patients with the tumor

47. • Therapy with Anti-Tumor Antibodies
• Tumor-specific monoclonal antibodies may be useful for specific immunotherapy
for tumors
• Currently, there are more than 100 different monoclonal antibodies being
considered, either in experimental animal studies or in human trials, as
therapeutic agents for cancer, and a few have been approved for clinical use
• Anti-tumor antibodies may eradicate tumors by the same effector mechanisms
that are used to eliminate microbes, including opsonization and phagocytosis,
activation of the complement system, and antibody-dependent cellular
cytotoxicity .
• These mechanisms are likely at work in B cell lymphoma patients treated with
anti-CD20 (rituximab), one of the most successful anti-tumor antibody
treatments to date

48. THE ROLE OF THE IMMUNE SYSTEM IN PROMOTING
TUMOR GROWTH
• Although much of the emphasis in tumor immunology has been on the role
of the immune system in eradicating tumors, it is clear that the immune
system may also contribute to the development of some solid tumors.
• In fact, chronic inflammation has long been recognized as a risk factor for
development of tumors in many different tissues, especially those affected
by chronic inflammatory diseases such as Barrett’s esophagus, Crohn’s
disease, pancreatitis, and prostatitis, for example.
• Some cancers associated with infections are also considered to be an
indirect result of the carcinogenic effects of the chronic inflammatory
states that are induced by the infectious organisms.
• These include gastric cancer in the setting of chronic Helicobacter pylori
infection and hepatocellular carcinomas associated with chronic hepatitis B
and C virus infection