TUMOR IMMUNOLGY

GROUP 4
Contents:
• Terminology and common types of cancer
• Malignant transformation
• Tumor antigen
• The immune response to cancer
• Cancer immunotherapy
• In most organs and tissues of a mature animal, a balance is usually
maintained between cell renewal and cell death.
• Under normal circumstances, the production of new cells is regulated
so that the number of any particular type of cell remains constant.
• Occasionally, though, cells arise that no longer respond to normal
growth-control mechanisms.
• These cells give rise to clones of cells that can expand to a
considerable size, producing a tumor, or neoplasm.
Terminology and Common Types
of Cancer
• Neoplasms :Cells that give rise to clones of cells that can expand in an
uncontrolled manner will produce a tumor
• Cancerous: term in which abnormal cells divide without control and
can invade nearby tissues
• benign Tumors can be benign (noncancerous). Benign tumors tend to
grow slowly and do not spread.
Continue
• Metastasis:uncontrolled growth, malignant tumor

• Malignant(cancerous). Malignant tumors can grow rapidly, invade and

destroy nearby normal tissues, and spread throughout the body.
• used to describe the spread of cancer cells from the primary tumor to
surrounding tissues and to distant organs
• often by way of the lymph system or bloodstream
• carcinomas, tumors that arise from epithelial origins such as skin, gut, or
the epithelial lining of internal organs and gland such as liver and kidney
• majority of cancers of the colon, breast, prostate, and lung are carcinomas
• Leukemia is cancer of the body's blood-forming tissues, including the bone
marrow and the lymphatic system
• Lymphoma is cancer that begins in infection-fighting cells of the immune
system, called lymphocytes.
• myeloma is a cancer that forms in a type of white blood cell called a
plasma cell.
• Leukemias proliferate as single detached
cells, whereas lymphomas and myelomas tend to grow as tumor
masses.

• Sarcomas, which arise less frequently and are derived from

mesodermal connective tissues, such as bone, fat, and cartilage
 Accute leukemia and chronic leokemia
• the leukemias were classified as acute or chronic according to the clinical progression of
the disease.
• Th e acute leukemias appeared suddenly and progressed rapidly, whereas the chronic
leukemias were much less aggressive and developed slowly as mild, barely symptomatic
diseases.
• major distinction between acute and chronic leukemias is the maturity of the cell involved.
• Acute leukemias tend to arise in less mature cells, whereas chronic leukemias arise in
mature cells.
• although each can arise from lymphoid or myeloid lineages. Th e acute leukemias include
acute lymphocytic leukemia (ALL) and acute myelogenous leukemia (AML). Th ese diseases
can develop at any age and have A rapid onset.
• The chronic leukemias include chronic lymphocytic leukemia (CLL) and chronic
myelogenous leukemia (CML), which develop more slowly and are seen primarily in adults.
Malignant transformation of cells
• Malignant transformation is the process by which cells acquire the
properties of cancer. This may in normal occur as a primary process l
tissue, or secondarily as malignant.
• chemical agents, irradiation, and certain viruses can alter the cell
Morphology and growth properties also leads to unregulated growth
and produces cells capable of growing as tumors when they are
injected into human Such cells are said to have undergone
transformation.
• Transformation can be induced by various chemical substances (such as
formaldehyde, DDT, and some pesticides), physical agents (e.g.,
asbestos), and ionizing radiation; all are linked to DNA mutations. For this
reason, these agents are commonly referred to as carcinogens
• Infection with certain viruses, most of which share the property of
integrating into the host cell genome and disrupting chromosomal DNA,
can also lead to transformation.
• Because of the variety of DNA repair mechanisms present in our cells,
exposure to carcinogens does not always lead to cancer. Instead, a
confluence of factors must occur before enough changes to normal
cellular genes occurs to induce malignant transformation. As we discuss
further in the following sections.
Oncogene
• An oncogene is a gene that has the potential to cause cancer.
• In tumor cells these genes are often mutated or expressed at high
levels.
• Normal cells will undergo programmed form of rapid cell death
(apoptosis) when critical functions are altered and malfunctioning.
• Activated oncogenes can cause those cells designated for apoptosis to
survive and proliferate .
• Most oncogenes began as proto-oncogenes: normal genes involved in
cell growth and proliferation or inhibition of apoptosis.
• If, through mutation, normal genes promoting cellular growth are up-
regulated (gain-of-function mutation), they will predispose the cell to
cancer; thus, they are termed "oncogenes". Usually multiple
oncogenes, along with mutated apoptotic or tumor suppressor genes
will all act in concert to cause cancer.
• Since the 1970s, dozens of oncogenes have been identified in human
cancer.
• Many cancer drugs target the proteins encoded by oncogenes.
 Genes Associated with Cancer Control Cell

Proliferation and Survival

• Normal tissues maintain homeostasis through a tightly regulated
process of cell proliferation balanced by cell death. An imbalance at
either end of the scale encourages development of a cancerous state.
• The genes involved in these homeostatic processes work by producing
proteins that either encourage or discourage cellular proliferation and
survival.
• The activities of these proteins can occur anywhere in the pathway,
from signaling events at the surface of the cell, to intracellular signal
transduction processes and nuclear event
• Each gene must have the correct instructions for making its protein.
This allows the protein to perform the correct function for the cell.
• All cancers begin when one or more genes in a cell mutate. A
mutation is a change. It creates an abnormal protein. Or it may
prevent a protein’s formation.
Types of genes linked to cancer
• Tumor suppressor genes. These are protective genes. Normally they
limit cell growth by:
• Monitoring how quickly cells divide into new cells
• Repairing mismatched
• DNA Controlling when a cell dies
• Tumor-suppressor genes, also known as antincogenes
• When a tumor suppressor gene mutates, cells grow uncontrollably.
And they may eventually form a tumor.
• Probably the single most frequent genetic abnormality in human
cancer, found in 60% of all tumors, is a mutation in the TP53 gene.
• This tumor-suppressor gene encodes p53, a nuclear phosphoprotein
with multiple cellular roles, including involvement in growth arrest,
DNA repair and apoptosis.
• Over 90% of small-cell lung cancers and over 50% of breast and colon
cancers have been shown to be associated with mutations in TP53.
• DNA repair genes. These fix mistakes made when DNA is copied.
Many of them function as tumor suppressor genes
• If a person has an error in a DNA repair gene, mistakes remain
uncorrected. Then, the mistakes become mutations

• Oncogenes. These turn a healthy cell into a cancerous cell. Mutations

in these genes are not known to be inherited.
• The proteins encoded by a particular oncogene and its corresponding
proto-oncogene have a very similar function
• A proto-oncogene is a normal gene found in the cell. There are many
proto-oncogenes. Each one is responsible for making a protein
involved in cell growth, division, and other processes in the cell.
• Most of the time, these genes work the way they are supposed to,
but sometimes things go wrong. If an error (mutation) in a proto-
oncogene, the gene can become turned on when isn’t supposed to be
turned on. If this happens, the proto-oncogene can turn into a
malfunctioning gene called an oncogene. Cells will start to grow out
of control. Uncontrollable cell growth leads to cancer
ROLE OF APOPTOTIC GENES
• Apoptotic genes: genes involve programmed cell death.
• Pro-apoptotic gene: act like tumor suppressor cells by inhabiting cell
survival.
• Antiapoptotic gene :act like ancogen promoting cell survival
• failure of former or over activity of antiaptotic gene can lead to
neoplastic transformation of cells
Stages of malignant transformation
The mutations progressively convert the cell from normal growth to a
precancerous state and fi nally a cancerous state,
Induction of malignant transformation appears to involve at least three
distinct phases
1.Initiation
2.Promotion
3.Progression
Initiation
• Initiation involves changes in the genome but does not in itself, lead
to malignant transformation.
• Initiation the first stage, is when initial cell mutation occurs. It may
involve one or more cellular changes that are either spontaneous or
started by exposure to a carcinogen. These changes create a potential
for the affected cell and its daughter cells to develop into a cancer cell
Promotion
• Promotion is the second stage where the transformed cells are
stimulated to divide. The environment within (intracellular) and
outside (extracellular) the cell influences cancer development.
Malignant transformation may involve more than one step and
requires repeated exposures to promoting agents. For example, one
tumor promoter is estrogen, a naturally occurring hormone that by
itself will not “initiate” cancer. However, estrogen can drive the
growth of a mutated breast cell.
 Progression

• Progression is the third stage. During progression, tumor cells

compete with another to survive, leading to more mutations that
make the cells more aggressive. As the tumor increases in size, the
cells undergo further mutations, leading to increased heterogeneity
within the tumor. Heterogeneity refers to multiple genetic variants of
the mutated or transformed cell. With increased heterogeneity, the
cancer cells found in one lump or mass can look and act differ- ently,
making diagnosis and treatment
 TUMOR ANTIGEN
• Is an antigenic substance produced in tumor cells. i.e it trigerrs an
immune response in the host.
• This antigens are not membrane proteins but are derivitives of
CYTOSOLIC PPROTEINS.
• Most tumor antigens give rise to peptides that are recognized by the
immune system following presentation by self major histocompatibility
complex (MHC) molecules.
• In fact, many of these antigens have been identified by their ability to
induce the proliferation of antigen-specific cytotoxic T lymphocytes
(CTLs) or helper T cells.
Tumor antigens recognized by human T cells fall into one of four groups
based on their source:

• Antigens encoded by genes exclusively expressed by tumors (e.g.,

viral genes)
• Antigens encoded by variant forms of normal genes that are altered
by mutation.
• Antigens normally expressed only at certain stages of development.
• Antigens that are overexpressed in particular tumors.
• There are two main types of tumor antigens, categorized by their
uniqueness:
1.Tumor-specific antigens (TSAs) and 2.Tumor-associated antigens
(TAAs). Originally these were designated as transplantation antigens.
 TUMOR SPECIFIC ANTIGENS
• TSAs are unique proteins that may result from mutations in tumor
cells that generate altered proteins and, therefore, new antigens.
Cytosolic processing of these proteins then gives rise to novel
peptides that are presented with class I MHC molecules inducing a
cell-mediated response by tumor-specific CTLs.
 TUMOR ASSOCIATED ANTIGENS
• TAAs are not unique to the cancer. Instead, these are represent
normal cellular proteins typically expressed only during specific
developmental stages such as in the fetus when the immune system is
immature and unable to respond but that normally are not expressed
in the adult..
• Those derived from mutation-induced reactivation of certain fetal or
embryonic genes are called oncofetal tumor antigens.
• Two well-studied oncofetal antigens are alpha-fetoprotein (AFP) and
carcinoembryonic antigen (CEA).
 The immune response to cancer.
• There are three proposed mechanisms by which the immune system is
thought to control cancer:
• By destroying viruses that are known to transform cells
• By eliminating pathogens and reducing pro-tumor inflammation
• By actively identifying and eliminating cancerous cells.
• The final mechanism involving tumor cell identification and eradication,
is termed as immunosurveillance. It posits that the immune system
continually monitors for and destroys neoplastic cells.
• Contemporary studies of immunity to cancer have now generated a more
nuanced hypothesis of immune involvement in neoplastic regulation.
• This model is called immunoediting; it incorporates observations of both
tumor-inhibiting and tumor-enhancing processes mediated by the immune
system.
• Cancer immunoediting process is envisaged to consist of three phases:
elimination, equilibrium, and escape.
• Elimination phase tumor cells are successfully recognized and
eliminated by the immune system, thus returning the tissues to their
normal state of function.
• Equilibrium phase where tumor expansion and metastasis are minimal
(tumor dormancy) and usually occur without symptoms.
• Tumors that are no longer susceptible to immune attack then progress
into the immunoediting process, termed “escape.” The emergence of
clinical symptoms of cancer generally correlates with the escape stage.
 Cancer immunotherapy
• Present-day cancer treatment can take many forms. Beyond surgery and
radiation treatment, which are most often employed in cases of larger more
discrete tumors, drug therapies can be used to target residual tumor cells
and to attack dispersed cancers.
• Drug therapy for cancer falls loosely into four categories:
• Chemotherapies aimed at blocking DNA synthesis and cell division.
• Hormonal therapies which interfere with tumor-cell growth.
• Targeted therapies such as small molecule inhibitors of cancer
• Immunotherapies which induce or enhance the antitumor immune
response.