immunology

immune responses
against tumors
Learning Outcomes (Cell mediated immunity)
✓ Understand the basics of tumor immunology, including the role of the immune system in
cancer surveillance and elimination.
✓ Identify different types of tumor antigens that are recognized as foreign by the immune
system.
✓ Discuss EVIDENCE FOR IMMUNE REACTIVITY against TUMORS.
✓ Differentiate between tumor specific, tumor associated, and Tumor associated
transplantation antigens.
✓ Explain IMMUNE MECHANISMS OF TUMOR REJECTION.
✓ Describe the mechanisms by which tumors evade immune detection and promote immune
tolerance.
Readings:
 Abbas, A.K. and Lichtman, A.H. (2005): Basic Immunology, 2nd ed. Elsevier, P. 131-132.
 Nairn, R. and Helbert, M (2005): Immunology for Medical Students, 2nd ed. Elsevier Mosby,
P. 24-30.
 Janeway and Travers Immunobiology: The immune
Dr. Ali Mohamed Eldib system in health and disease
 Introduction
Cancer immunology is concerned with the
role of the immune system in the
progression and development of cancer;
the most well-known application is cancer
immunotherapy, where the immune
system is used to treat cancer.
Cancer immunosurveillance is a theory formulated in 1957 by Burnet and Thomas,
who proposed that lymphocytes act in recognizing and eliminating continuously
arising transformed cells. Cancer immunosurveillance appears to be an
important host protection process that decreases cancer rates through inhibition
of carcinogenesis and maintaining of regular cellular homeostasis.
MALIGNANT TRANSFORMATION
The proliferation of normal cells is carefully
regulated. However, such cells when exposed to
chemical carcinogens, irradiation and certain viruses
may undergo mutations leading to their
transformation into cells that are capable of
uncontrolled growth, producing a tumor or
neoplasm. Dr. Ali Mohamed Eldib
A tumor may be:
Benign, if it is not capable of indefinite growth and the
host survives.
Malignant, if the tumor continues to grow indefinitely and
spreads (metastasizes). This uncontrolled growth may be
due to up regulation of oncogenes (cancer-inducing
genes) and/or down regulation of tumor suppressor
genes (that normally inhibit tumor growth often by
inducing cell death). Dr. Ali Mohamed Eldib
Immune responses:
The antigens that mark tumors as foreign may be expressed in any cell type
that is the target of malignant transformation.
Therefore, there have to be special mechanisms for inducing immune responses
against diverse cell types. Also, an important, and perhaps major, mechanism
by which tumor cells are destroyed involves cytotoxic T lymphocytes (CTLs).
What are the tumor antigens that are recognized as foreign by the immune
system?
How does the immune system recognize and react to tumors ?
How can the immune responses to tumors be manipulated to enhance tumor
rejection?
Dr. Ali Mohamed Eldib
Evidence for Immune Reactivity Against Tumors:
1.Immunogenic Tumor Mutations (Neoantigens): Some tumors accumulate
mutations that result in the expression of neoantigens, which are recognized as
foreign by the immune system. The presence of neoantigens can lead to the
activation of an immune response against the tumor.
2.Spontaneous Tumor Regression: In rare cases, tumors can undergo spontaneous
regression, where they shrink or disappear without treatment. This phenomenon
is thought to be mediated by an immune response against the tumor.
3.Cancer Immunoediting: Cancer immunoediting is a process by which the
immune system can recognize and eliminate cancer cells. This process consists of
three phases: elimination, equilibrium, and escape, highlighting the dynamic
interaction between the immune system and
Dr. Ali Mohamed Eldibtumors.
4.Immune Checkpoint Inhibitor Therapy Response: Immune checkpoint
inhibitors, which block inhibitory signals in the immune system, have
shown remarkable efficacy in treating various cancers. The response to
these therapies provides direct evidence of immune reactivity against
tumors.
5.Cytokine Production: The production of cytokines, such as interferons and
interleukins, by immune cells within the tumor microenvironment can
indicate an active immune response against the tumor.
6.Tumor Antigen-Specific T Cell Responses: Detection of tumor antigen-
specific T cell responses in peripheral blood or within tumors indicates that
the immune system is actively recognizing and targeting tumor cells.
Dr. Ali Mohamed Eldib
7.Clinical Observations: Clinical observations, such as increased survival in
patients with higher levels of tumor-infiltrating lymphocytes or the
occurrence of autoimmune phenomena in cancer patients, provide indirect
evidence of immune reactivity against tumors.
8.Tumor-Infiltrating Lymphocytes (TILs): TILs are a type of immune cell that
can infiltrate tumors. The presence of TILs, particularly cytotoxic T cells,
within tumors is associated with better prognosis in various types of cancer,
indicating an ongoing immune response against the tumor.
9.Animal Models: Studies in animal models have demonstrated that the
immune system can recognize and eliminate tumors, providing further
evidence of immune reactivity against tumors.
Dr. Ali Mohamed Eldib
Dr. Ali Mohamed Eldib
 Basics of Tumor Immunology

Cancer Immunosurveillance:
• The immune system continuously monitors the body for abnormal cells, including cancer cells,
through a process called immunosurveillance. Specialized immune cells, such as cytotoxic T cells
and natural killer (NK) cells, play a central role in detecting and eliminating these abnormal cells.
Recognition of Cancer Cells:
• Cancer cells can express abnormal proteins or antigens that are recognized as foreign by the
immune system. Antigen-presenting cells (APCs) process these antigens and present them to T
cells, initiating an immune response against the cancer cells.
3. Immune Response to Cancer:
•Upon recognition of cancer cells, T cells become activated and multiply, leading to the formation
of effector T cells that directly attack and kill the cancer cells.
•NK cells can also recognize and kill cancer cells
Dr. Ali directly,
Mohamed Eldib without the need for prior sensitization..
Immune Checkpoints:
&
• To prevent overactivation of the immune system and maintain self-tolerance, immune
checkpoints, such as PD-1 (programmed cell death protein 1) and CTLA-4 (cytotoxic T-
lymphocyte-associated protein 4), regulate immune responses. However, cancer cells can
exploit these checkpoints to evade immune detection and elimination.
Tumor Immune Evasion:
•Cancer cells can evade immune detection and elimination through various mechanisms, such
as downregulating the expression of antigens or MHC molecules. They can also produce
immunosuppressive molecules or recruit immune suppressor cells, such as regulatory T cells
and myeloid-derived suppressor cells, to the tumor microenvironment.
Immunotherapy in Cancer Treatment:
•Immunotherapy aims to enhance the immune system's ability to recognize and eliminate
cancer cells.
Dr. Ali Mohamed Eldib
 The Interaction of the Immune System with Cancer
(cancer immunoediting)
Cancer development involves
a complex interplay between
cancer cells and the immune
system, which can be
characterized by three
phases: elimination,
equilibrium, and escape. This
dynamic process, known as
cancer immunoediting,
illustrates the complex
relationship between cancer
and the immune system. Dr. Ali Mohamed Eldib
1. Elimination Phase:
•The immune system recognizes and
eliminates cancer cells before they
become clinically apparent.
2. Equilibrium Phase:
•In some cases, cancer cells can evade complete elimination and enter a state of
equilibrium with the immune system. During this phase, the immune system
keeps the tumor in check, preventing its growth and spread.
3. Escape Phase:
•Despite the immune system's efforts, cancer cells can eventually develop
mechanisms to escape immune recognition and destruction.
Dr. Ali Mohamed Eldib
TUMOR ANTIGENS
Tumor antigens play a critical role in cancer immunoediting, the process by which the immune
system interacts with tumor cells, leading to either elimination, equilibrium, or escape. These
antigens can be classified into several types based on their origin, expression pattern, and role
in cancer immunoediting

Tumor antigens that are recognized by tumor-specific

CD8+ T cells may be mutated forms of normal self
proteins, products of oncogenes or tumor suppressor
genes, overexpressed or aberrantly expressed self
proteins, or products of oncogenic viruses.
Tumor antigens also may be recognized by CD4+ T cells,
but less is known about the role that CD4+ T cells play
in tumor immunity.
Dr. Ali Mohamed Eldib
1.Cancer Testis Antigens (CTAs):
Origin: CTAs are typically expressed in normal testis tissue but aberrantly
expressed in various cancer types.
Role: They play a key role in eliciting immune responses against cancer cells
and are considered potential targets for cancer immunotherapy due to their
restricted expression pattern.
2. Overexpressed Antigens:
Origin: These antigens are derived from proteins that are overexpressed in
tumor cells compared to normal tissues.
Role: They can elicit immune responses due to their increased abundance in
cancer cells, making them attractive targets for immunotherapy approaches
such as cancer vaccines and adoptive T cell therapy.
3. Mutation Antigens:
Origin: Mutation antigens arise from somatic mutations in tumor cells, leading
to the expression of neoantigens that are absent in normal tissues.
Role: Mutation antigens are highly specific to individual tumors and can
trigger potent immune responses. They are considered promising targets for
personalized cancer immunotherapy strategies, such as neoantigen-based
vaccines and T cell therapies.
4. Cancer-associated Antigens:
Origin: These antigens are associated with cancer cells and may include
proteins that are involved in cell proliferation, survival, and metastasis.
Role: Cancer-associated antigens are frequently targeted by the immune
system and can serve as biomarkers for cancer diagnosis and prognosis.
5. Tumor Developmental (Oncofetal) Antigens:
Origin: Oncofetal antigens are proteins normally expressed during embryonic
development but re-expressed or overexpressed in tumor cells.
Role: They can elicit immune responses due to their aberrant expression in
cancer cells. Oncofetal antigens such as alpha-fetoprotein (AFP) and
carcinoembryonic antigen (CEA) are commonly used as biomarkers for certain
types of cancer and may also be targeted for immunotherapy.
6. Tumor-associated Transplantation Antigens (TATA):
Origin: TATA are antigens derived from proteins that are aberrantly
expressed or mutated in tumor cells.
Role: They can serve as targets for immune recognition and response, playing
a role in immune surveillance and tumor rejection.
Other possible tumor antigens include
viral antigens (derived from oncogenic
viruses such as human papillomavirus and
hepatitis B virus), glycoproteins,
glycolipids, and heat shock proteins that
are upregulated in response to cellular
stress in tumor cells.
 IMMUNE MECHANISMS OF TUMOR REJECTION
The principal immune mechanism of tumor
eradication is killing of tumor cells by CTLs
specific for tumor antigens. A majority of
tumor antigens that elicit immune responses
in tumor-bearing individuals are
endogenously synthesized cytosolic proteins
that are displayed as class I major
histocompatibility complex (MHC)–
associated peptides.
CTLs also need co-stimulation and/or help from class II MHC–restricted CD4+ T
cells. Dr. Ali Mohamed Eldib
EVASION OF IMMUNE RESPONSES BY TUMORS:
Immune responses may fail to stop tumor growth,
because these responses are ineffective or
because tumors evolve to evade immune attack.
1- Immune responses against tumors may be weak
because many tumor antigens are weakly
immunogenic,
2- Growing tumors also develop mechanisms for
evading immune responses. Some tumors stop
expressing the antigens that are the targets of
immune attack. These tumors are called “antigen
Dr. Ali Mohamed Eldib
loss variants.”
3. Other tumors stop expressing class I MHC molecules. So, they cannot
display antigens to CD8+ T cells. NK cells recognize molecules expressed
on tumor cells, but not on normal cells, and are activated when their
target cells lack class I MHC molecules. Therefore, NK cells may provide a
mechanism for killing class I MHC–negative tumors.
4. Other tumors may secrete cytokines, such as transforming growth
factor-β, that suppress immune responses.
5. Some tumors engage normal T cell inhibitory pathways, such as those
mediated by CTLA-4 or PD-1, and thus suppress anti-tumor immune
responses.
Dr. Ali Mohamed Eldib
IMMUNOLOGICAL APPROACHES FOR CANCER THERAPY
The main strategies for cancer immunotherapy aim to provide
antitumor effectors (antibodies and T cells) to patients, actively
immunize patients against their tumors, and stimulate the patients’
own antitumor immune responses.
At present, the treatment of cancers (which cannot be surgically
resected) relies on chemotherapy and irradiation, both of which have
devastating effects on normal non-tumor tissues. Because the immune
response is highly specific, it has long been hoped that tumor-specific
immunity may be used to selectively eradicate tumors without injuring
Dr. Ali Mohamed Eldib
the patient.
1- Monoclonal antibodies against various tumor antigens, often
coupled to potent toxins, have been tried in many cancers. The
antibodies bind to tumor antigens and either activate host effector
mechanisms, such as phagocytes or the complement system, or
deliver the toxins to the tumor cells.
2- Other monoclonal antibodies that are used in cancer therapy
may work by blocking growth factor signaling (e.g., anti-Her2/Neu
for breast cancer) or by inhibiting angiogenesis (e.g., antibody
against the vascular endothelial growth factor for colon cancer and
other tumors).
Dr. Ali Mohamed Eldib
3- T lymphocytes may be isolated from the blood or
tumor infiltrates of a patient, expanded by culture
with growth factors, and injected back into the same
patient. The T cells presumably contain tumor specific
CTLs, which find the tumor and destroy it. This
approach, called “adoptive cellular immunotherapy,”
has been tried as a therapy for several types of
metastatic cancers, but results have been variable
among different patients and tumors.
Dr. Ali Mohamed Eldib
4- Many new strategies for cancer immunotherapy rely on boosting
the host’s own immune responses against tumors. One way of
stimulating immune responses against tumors is to vaccinate
patients with their own tumor cells or with antigens from these cells.
5- Immune Checkpoint Inhibitors: By targeting inhibitory pathways
that regulate T cell activation and function. Key checkpoint molecules
targeted by ICIs include programmed cell death protein 1 (PD-1),
programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4). By blocking these inhibitory signals
Dr. Ali Mohamed Eldib
6- Another approach to vaccination uses a plasmid containing a
complementary DNA (cDNA) encoding a tumor antigen.
7- Tumors caused by oncogenic viruses can be prevented by
vaccinating against these viruses. Two such vaccines that are
proving to be remarkably effective are against hepatitis B virus (the
cause of many liver cancers) and human papillomavirus (the cause
of cervical cancer).
8- Treat patients with cytokines that stimulate immune responses.
The first cytokine to be used in this way was interleukin-2 (IL-2), but
its applications are limited by serious toxic effects at the high doses.
Dr. Ali Mohamed Eldib
Dr. Ali Mohamed Eldib