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Immunology Lecture 11 Ashraf Khasawneh Faculty of Medicine The Hashemite University

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Introduction to tumors types and aetiology Tumors associated antigens and markers Evidence for Immune Reactivity to Tumors  Discuss immune protection against tumors and immune surveillance system  Discuss immune mediated tumor growth  Provide an overview of experimental cancer therapies

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Pathological cell masses derived by abnormal and uncontrollable clonal expansion of a single cell Cells that continue to replicate, fail to differentiate into specialized cells, and become immortal.   Cells become antigenically different from normal cells  They are recognized and destroyed by immune system Tumors can be: Malignant: A tumor that grows indefinitely and spreads (metastasis)--also called cancer: kills host Benign: A tumor that is not capable of metastasis: does not kill host

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Carcinoma:  arising from epithelial tissue, such as glands, breast, skin, and linings of the urogenital, digestive, and respiratory systems (89.3% of all cancers)  Sarcoma:  solid tumors of muscles, bone, and cartilage that arise from the embryological mesoderm  (1.9% of all cancers) Leukemia:  disease of bone marrow causing excessive production of leukocytes (3.4% of all cancers)  Lymphoma, Myeloma:  diseases of the lymph nodes and spleen that cause excessive production of lymphocytes (5.4% of cancers)

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Inherited : Expression of inherited oncogene: Breast, colon, prostate cancers Viral: Viral genome incorporated into host gene Human papilloma, herpes type 2, HBV, EBV (DNA ( Human T-cell leukemia virus   (RNA) Chemical: Poly cyclic hydrocarbons cause sarcomas Aromatic amines cause mammary carcinoma  Alkyl nitroso amines cause hepatoma Radiological: Ultraviolet & ionizing irradiation Spontaneous: failure in the cellular growth control

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Targeting TSA and TAA
CrownBio
TAA
Tu mor cell
APM
TAA Expression
Tumor-Associated Antigens
PD-LI
Neoantigen
PD-LI
Tumor cell
• APM
TSA Expression
Tumor-Specific Antigens
Overexpressed proteins,
differentiation antigens
VARIABLE
HIGH
HIGH
Cancer testis
antigens
Target
Tumor
specificity
Central
tolerance
Prevalence
in multiple
patients
Oncoviral
antigens
Shared
Neoantigens
IDEAL
NONE
Private
Neoantigens
HIGH

Viral Antigen:  Viral proteins and glycoproteins      New antigens produced by virally infected host  cells under control of viral nucleic acid  Tumor specific antigens:  Tumor cells develop new antigen specific to their carcinogen Tumor specific transplantation antigens:  Tumor cells express new MHC antigens due to  alteration of normally present MHC antigens Oncofetal antigens: Carcino -embryonic antigens (CEA) Normally expressed during fetal life on fetal gut Reappearance in adult life: GIT, pancreas, biliary system and breast cancers   Alpha fetoprotein: Normally expressed in fetal life  Reappearance in adult life; hepatoma

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Evidence for Immune Reactivity  to Tumors

Tumors that have severe lympho -reticular infiltration have a better prognosis than those that do not.   Certain tumors regress spontaneously  There is an increased incidence of primary and secondary malignancies (particularly lympho-reticular tumors) in immunodeficient patients   Antibodies and immune T lymphocytes have been detected in patients with tumors.   The young and the very old have an increased occurrence of tumors.   Finally, animals can be specifically immunized against various types of tumors

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Animal models showed that pre-treatment of mice with killed tumour material could protect against a subsequent challenge. T cell ablation or T-cell deficient mice removed this protection. Transfer of T cells from an immunized mouse could protect a naïve mouse from tumour challenge. (Adoptive immunotherapy)

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During neoplastic transformation, new antigen develop The host recognize them as non-self antigens Cell mediated immune reactions attack these non-self tumor cells Immune response act as surveillance system to detect and eliminate newly arising neoplastic cells

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This system include :  1) Natural killer (NK) cells      They kill directly tumor cells, helped by interferon, and IL-2  2)  Cytotoxic  T-cells      They also kill directly tumor cells  3) Cell mediated T-cells ( effector  T-cells)    They produce and release a variety of  lymphokines  :     a-Macrophage activation factor that activate macrophages    b-Gamma interferon and interleukin-2 that activate NK    c-Tumor necrosis factor ( cachectine ):  apoptosis, necrosis, immune cell activation, differentiation, and cell migration.

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4) B-cells : Tumor associated antigens stimulate production of  specific antibodies by host B-cells These specific antibodies bind together on tumor cell surface leading to destruction of tumor through: Antibody mediated- cytotoxicity  :  Cytotoxic  T-cells  kill     IgG -coated tumor cells Activation of macrophages: Sensitized T-cells release  macrophage activating factor  which activate macrophages Activation of classical pathway of complement leading to  Lysis  of tumor cells

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Mechanisms by which tumor escape immune defenses: 1)  Reduced levels or absence of MHCI molecule on tumor cells so that they can not be recognized by CTLs  2)  Some tumors stop expressing the antigens  ( not essential for tumor growth)      These tumors are called “antigen loss variants” 3)  Production of immunosuppressive factors by tumor e.g. transforming growth factor (TGF-β) :  the early stages it inhibits cellular transformation and prevents cancer progression. In later stages TGF-β plays a key role in promoting tumor progression through mainly 3 mechanisms: facilitating epithelial to mesenchymal transition, stimulating angiogenesis and inducing immunosuppression 4)  Tumor antigens may induce specific immunological tolerance :  state of unresponsiveness of the immune system to substances or tissue that have the capacity to elicit an immune response in a given organism.

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5) Tumor cells have an inherent defect in antigen processing and presentation  6) Blocking of receptors on T-cells by specific antigen antibodies complex (after shedding of tumor Ag) prevents them from recognizing and attacking  tumor cells 7) Antigens on the surface of tumors may be masked by sialic acid-containing mucopolysaccharides 8) Immune suppression of the host as in transplant     patients who show a higher incidence of malignancy

A Fucme
Sidic
C]GdNAc
oec
Sialylated tumour
associated glycans
GD2
sTn
Sialylated
N-glycans
s LeA0rx

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Anything present in or produced by cancer cells or other cells of the body in response to cancer or certain benign (noncancerous) conditions that provides information about a cancer Tumor markers : They are either   Tumor antigens diagnose,  stage , and/or classify cancer estimate prognosis select an appropriate treatment  Tumor products (enzymes and hormones)  found in the blood, urine, stool, or other bodily fluids of some patients with cancer USED TO: E stimate  prognosis D etermine the  stage  of cancer D etect cancer that remains after treatment ( residual disease ) or that has returned after treatment A ssess how well a treatment is working M onitor whether the treatment has stopped working

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1) Alpha fetoprotein antigen (AFP) in cases of  hepatoma  2)  Carcinoembryoinic  antigen (CEA) in gastrointestinal tumors, tumors of biliary system and cancer breast  3) Cancer antigen 125 (CA 125) in ovarian carcinoma  4) Cancer antigen 15-3 (CA15-3) in breast cancer  5) Cancer antigen 19-9 in colon and pancreatic tumor  6) Prostatic specific antigen (PSA) in prostatic tumors

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a) Hormones:      Human chorionic  gonadotrophins  (HCG) are secreted            in cases of  choriocarcinoma      Thyroxin (T3 & T4) is secreted in cases of cancer              of thyroid gland   b) Enzymes:     Acid phosphatase enzymes in cases of cancer prostate     Alkaline phosphatase, lipase and amylase enzymes in cases of pancreatic cancer

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Diagnosis:  Immunodiagnostics is a diagnostic methodology that uses an antigen-antibody reaction as their primary means of detection. Monoclonal antibodies labeled with radioisotope have been used for in vivo detection of relatively small tumor foci. Antibodies have also been used in vitro to identify the cell origin of undifferentiated tumors, particularly of lymphocytic origin. Immuno-histological staining is used to confirm suspected metastatic foci, especially in bone marrow

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Treatment (immune therapy):  Immunotherapy is a type of cancer treatment that helps your immune system fight cancer. T-cell transfer therapy , which is a treatment that boosts the natural ability of your  T cells  to fight cancer. In this treatment, immune cells are taken from your tumor. Those that are most active against your cancer are selected or changed in the lab to better attack your cancer cells, grown in large batches, and put back into your body through a needle in a  vein.T -cell transfer therapy may also be called adoptive cell therapy, adoptive immunotherapy, or immune cell therapy. Monoclonal antibodies , which are immune system proteins created in the lab that are designed to bind to specific targets on cancer cells. Some monoclonal antibodies mark cancer cells so that they will be better seen and destroyed by the immune system. Such monoclonal antibodies are a type of  immunotherapy.Monoclonal  antibodies may also be called therapeutic antibodies. Treatment vaccines , which work against cancer by boosting your immune system’s response to cancer cells. Treatment vaccines are different from the ones that help prevent disease.  Immune system modulators , which enhance the body’s  immune response  against cancer. INF, ILs, EPO, GM-CSF, and BCG. Immune checkpoint inhibitors , which are drugs that block immune checkpoints.

PD.LI binds to PD-I and inhibits
T cell killing of tumor cell
Tumor cell
PD.LI
—T cell receptor
Blocking PD-LI or PD.I allows
T cell killing of tumor cell
Tumor Cen
Anti.PD.L1
PD.I
PD.I
T cell

Checkpoint proteins, such as PD-L1 on tumor cells and PD-1 on T cells, help keep immune responses in check. The binding of PD-L1 to PD-1 keeps T cells from killing tumor cells in the body (left panel). Blocking the binding of PD-L1 to PD-1 with an immune checkpoint inhibitor (anti-PD-L1 or anti-PD-1) allows the T cells to kill tumor cells (right panel).

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Type of vaccine
Killed tumor
Purified tumor antigens
Cytokine and costimulator-
enhanced
DNA
Viral vectors
Vaccine preparation
killed tumor cells + adjuvants
tumor cell lysates + adjuvants
Melanoma antigens
Heat shock proteins
DC pulsed with TAA
DC transfected with TAA
Cytokine or B7 gene transfected tumor cells
APC transfected with cytokines and pulsed with
TAA
plasmids encoding TAA
Adenovirus, vaccinia virus encoding TAA +1-
cytokines
Clinical trials
Melanoma, colon cancer
Melanoma
Melanoma
Melanoma, renal cancer, sarcoma
Various
Various
Melanoma
Melanoma

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Vaccinate with
tumor-antigen
pulsed
dendritic cell
Dendritic cells
pulsed with
tumor antigens
Plasmid expressing
cDNA encoding
tumor antigen
Vaccinate
with DNA or
transfected
dendritic cell
CD8+
T cell
CD8+
T cell
Dendritic cells
transfected with
plasmid expressing
tumor antigen
APC producing
tumor antigen
@ Elsevier. Abbas et al: Cellular and Immunology 6e - www.studentconsult.com
Activation of
tumor-specific
T cells
O
Activation of
tumor-specific
T cells

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Tumor-specific
antibody
Antibodies bind to the
tumor cell
CD16
NK cells with Fc receptors
(CD16) are activated to kill
the tumor cells
Tumor-specific antibody
conjugated to toxin
Antibody-toxin conjugates
bind to the tumor cell
Conjugates are internalized,
killing the cell
Tumor-specific antibody
conjugated to radioisotope
Radioactive antibody
binds to the tumor cell
Radiation kills the tumor cell
and neighboring tumor cells
Figure 14-17 Immunobiology, 6/e. (O Garland Science 2005)

Tumor Immunology

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