Tumor Immunology

Cruz, Carl Dustin T.

Khan, Samina Cousir A.
3HMT

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 What is Tumor Immunology?

The Study Of:

the antigens associated with tumors

the immune response to tumors

The effect of the tumor on the
host’s immune status

The use of the immune system to

help eradicate the tumor.

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 What are tumor?

Neoplasm
Result from the new growth of cells
(neoplasia) that proliferate in an
uncontrolled manner.

BENIGN or MALIGNANT.

manifest tumor antigens, as

well as “self” HLA antigens

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 BENIGN MALIGNANT
“oma” Carcinoma

Usually encapsulated Increase in the number of

cells that proliferate
Slow growth
Invasion of tissues
Non spreading
Metastasis
Minimal mitotic activity
Characteristic nuclear
Resembles the parent tissue cellular feature

Do not cause death

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 MALIGNANT CELLS

undergo physiologic changes such as:

• Perpetual reproduction

• Loss of contact inhibition

• Altered antigenic compositio

cells

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CAUSES OF CANCER

Environmental associations (e.g. Chemical and

radiation)

Host factors and disease associations

(e.g. Cirrhosis)

Viruses (e.g. Epstein-Barr virus)

Some are unknown

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 IMMUNOSURVEILANCE
•immune system identifies and kills tumor cells

•Cancers which come to medical attention are

only those that have managed to evade the
immune system

•The immune system can only target the

tumor mass if it is seen as foreign.

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 TUMOR INFILTRATING LYMPHOCYTE
(TIL)

• react with the

antigens on the
tumor
– Indicating the
presence of
cellular immune
response to the
tumor

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Experimental Evidence for Tumor Antigens and
Immune Response

1. Inject Tumor 2. Excise tumor 3. Re-challenge with 4. No tumor

same tumor growth

1. Inject Tumor 2. Excise tumor 3. Re-challenge with 4. Tumor

different tumor grows
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 TUMOR ANTIGENS
produced by tumors

produced in response to
a tumor

used to screen for

cancer
monitor recurrence of cancer

Determine the degree of tumor burden

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TUMOR ANTIGENS

Tumor Specific Antigens (TSA)

Tumor Associated Antigens (TAA)

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Tumor Associated Tumor Specific Antigens
Antigens (TAA) (TSA)
• May be found in normal • Expressed only in the
tissues Tumor
• Not immunogenic • Immunogenic
• Quantity is proportional • Not present in normal cells
with tumor growth
TUMOR ASSOCIATED
MARKER FOR:
ANTIGENS

Bence-Jones Protein Multiple myeloma

Monoclonal immunoglobulin Multiple myeloma

Beta – Human chorionic gonadotropin

Testicular tumor
(β – hCG)

Familial medullary thyroid carcinoma

Calcitonin
Multiple endocrine neoplasia type 2A.

Prostate Specific Antigen (PSA) Prostate cancer

Alpha Feto Protein (AFP) Hepatocarcinoma

Carcinoembryonic Antigen (CEA) Gastro intestinal carcinoma Page 13

OTHER TAA
INCLUDE:
Prostatic Acid Phosphatase Prostatic Cancer

S-100 calcium-binding protein Melanoma

CA-125 glycoprotein Ovarian Cancer

CA-19-9 glycoprotein Pancreatic Cancer

CA-15-3 glycoprotein Breast and Lung Cancer

CA-27-29 Breast carcinoma

Human Placental Lactogen (hPL) Trophoblastic neoplasms

Acid Kinase Stomach Cancer

Alkaline Phosphatase Bone Cancer

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VIRUS INDUCED TAA

Epstein- Bar virus (EBV) antigen Burkitt’s lymphoma

Nasopharyngeal carcinoma

Hepatitis B Primary liver cancer

Human papilloma viruses 16 and 19 Cervical cancer

Human T- cell lukemia virus Adult T cell Lukemia

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 ONCOFETAL
PROTEINS
PRESENT DURING NORMAL FETAL
DEVELOPMENT

LOST DURING DIFFERENTIATION OF FETAL TISSUE

NOT SYNTHESIZED BY ADULTS

REAPPEAR WITH THE

DEVELOPMENT OF MALIGNANCY
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ALPHA FETO PROTEIN (AFP)
secreted during fetal development

synthesized by fetal liver cells

secreted in the serum with

 Hepatocarcinoma

 endodermal sinus tumor

 nonseminatous testicular cancer

 teratocarcinoma of the testis and ovary

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 VIRUS INDUCED TAA
Epstein- Bar virus (EBV antigen)
Burkitt’s lymphoma

Nasopharyngeal carcinoma

Hepatitis B
Primary liver cancer

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 Human papilloma viruses 16 and 19

Cervical cancer

Human T- cell lukemia virus

Adult T cell Lukemia

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 Tumor Specific Transplantation Antigens (TSTA)

• Antigens that can induce a protective immune

response in the host if they occur on the
membrane of the malignant cell

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IMMUNOLOGIC RESPONSE
TO TUMORS

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 MACROPHAGES

Mechanism same as those activated response

to infectious diseases

IgG antibodies on tumor cells can facilitate

opsonin mediated phagocytosis
 Phagocytes express FcγR receptor

secretes tumor necrosis factor (TNF)

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 NATURAL KILLER CELLS (NK)

Lyse certain tumor cell lines following direct

interaction of their target

same mechanism of as CTL’s in killing cells but do

not express T-cell antigen receptor

recognize cells that fail to express MHC

class I molecules

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NATURAL KILLER CELLS (NK)

Release of Perforin
to induce lysis

Tumoricidal activity of NK cells is

enhanced with Type 1 cytokines

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 B CELLS and ANTIBODIES
• Not direct effectors of immunity

• Antigen recognition

• Followed by B cell activation and differentiation to plasma cell

– Secreted antibodies are the immunologic effectors

• IgG antibodies that have targeted a cancer cell serve as an

indirect link for opsinin mediated phagocytosis or ADCC
killing by natural killer cells

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 B CELLS and ANTIBODIES
Not direct effector of immunity

Antigen recognition

Followed by B cell
activation and
differentiation to
plasma cell

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Both IgM and IgG antibodies have been
shown to destroy tumor cells in vitro

Activates the classsical pathway

Generating complement fragement C3b

 serves as an opsonin

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 Role of T LYMPHOCYTES

Cell mediated response Cytotoxic T-cell (CD8 T cell)

• Destruction of virally induced tumors

– Cytokines are essential in anti tumor response

• IFN-α
• TNF
• CD4 Helper T cell
– Plays a major role in the induction, regulation and maintenance
of such CTLs

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 EFFECTOR MECHANISMS IN
CANCER IMMUNITY
EFFECTOR MECHANISM COMMENTS

Antibodies and B cells (Complement- Role in immunity poorly uderstood

mediated lysis, opsonization)

T cells (cytolysis, ADCC, apoptosis) Rejection of virally and chemically

induced tumors

NK cells (cytolysis, apoptosis) Antitumor responses

Macrophage and Neutrophils (cytostasis, Destroy or inhiibit tumor cell growth

cytolysis, phagocytosis)

Cytokines (apoptosis, recruitment of Growth inhibition

inflammatory cells)
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 MECHANISMS BY WHICH TUMORS
EVADE THE IMMUNE SYSTEM
TUMOR ANTIGEN MHC T CELL
RELATED RELATED RELATED

Antigen Hole in the repertoire

Masking Determination
selection
Lack of type I cytokines

Antigen
Shedding
Lack of constimulatory
molecules
Loss of cell
surface
Mutations of
mutations expression Absence of CD4+ T cell
activation

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 TUMOR ANTIGEN RELATED
• Tumor cells express Carbohydrates on their
surface Tumor Antigens on these cells
cannot be “Seen”

• Tumor Antigens are shed Antibodies will

form complexes with these soluble antigens
Tumor cells escape.

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 MHC RELATED

• LOSS OF CLASS I MHC CELL SURFACE

EXPRESSION:
• Absence of class I MHC-tumor antigen peptide complexes
on the cell not recognized by CD8+ T cells and can
only be targeted by NK cells

• DETERMINANT SELECTION
• Applied to both tumor cells and antigen presenting cell
• Absence of appropriate MHC capable of forming a
complex with a tumor peptide peptide-MHC
complex NOT PRESENTED TO T CELLS.
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 T CELL RELATED
MECHANISMS
• ABSENCE OF ANTIGEN SPECIFIC
RECEPTORS:

• HOLE IN THE REPERTOIRE

» MHC-Tumor antigen peptide complexes are
formed, displayed but the individual LACKS
T CELLS with with appropriate receptors

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• LACK OF TYPE 1 CYTOKINES:
–IL-2 SECRETED BY CD4+ T CELLS

–Absence of Type 1 Cytokines

CD8+ T cells will not be
activated.

–Type 2 cytokines suppress production

of Type 1 cytokines

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• ABSENCE OF CD4+ T CELL ACTIVATION

– Antigen peptide – Class II MHC complex

must be formed and expressed on the APC
surface, a process that requires endocytosis
and processing.

– Tumor antigens must be shed before CD4+ T

cells can be activated.

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(a) After transformation of cells in a normal layer (diamond-shaped cells) into cancerous cells (with irregular shapes), attack by
various different cell types of the immune system (indicated by round cells) may lead to elimination of the cancerous cells. (b) If
elimination is unsuccessful, the immune system and the cancer can reach an equilibrium in which immune cells keep the cancer in
check but cannot remove it completely. During the elimination phase, there is selection on the cancer cells, whose genomes are also
unstable. This can lead to escape (c), in which mutated cancer cells become able to inhibit the immune system. The cancer can then
grow unchecked. Figure modified from [2]. CD4+, CD8+, CD4+CD25+ Treg, γδ and NKT cells are all types of T cell; Mφ cells are
macrophages and NK cells are natural killer cells.
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 TELOMERES
• repetitive DNA sequences at the end of linear
chromosomes

• Shortening is observed each time a cell divides

• When telomeres are short, cells stop dividing

and undergo a growth arrest (called replicative
senescence).

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 TELOMERASE
• a cellular reverse transcriptase that stabilizes
telomeres

• cells and their offspring become immortal

• allows cancer cells to divide virtually forever,

which is why they can form tumors.

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 TELOMERASE AS A
DRUG TARGET
• telomerase is necessary for the immortality

• . If a drug can be used to turn off telomerase in

cancer cells:
• process of telomere-shortening will resume
• telomere length will be lost as the cells continue to
divide, mutations will occur, and cell stability will
decrease

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