tumor immunology 2022.ppttumor Immunology

tumor Immunology

1. Prof Dr Naael H Ali,
لئان روتكدلا ذاتسلأا
يلع نيسح
Clinical Immunology
College of Medicine
University of Basrah

2. Content:
• Cancer VS Tumor
• Immune surveillance
Tumor antigens
• Immune evasion
• Tumor immunotherapy

3. Introduction
Cell growth & cell death are normally balanced
so that a stable number of cells are maintained
in a given tissue. Occasionally, however, cells
arise that no longer respond to the usual checks
and balances for division and death. These are
tumor cells.

4. Not all tumors are cancerous
A tumor may or may not develop into cancer. Cancer on the other
hand is a malignant condition in which the spread of abnormal
cellular growth could become uncontrollable.

5. Altered self cells
Unregulated mitosis
Produces tumor (neoplasm)
Benign – does not invade healthy tissue
Malignant – grows and becomes invasive
Exhibit metastasis

6. What causes dysregulated cell growth
& proliferation?
• Intrinsic factors - Genetic mutations on oncogenes and
Tumor suppressor genes
• Environmental factors – Radiation, Carcinogens
• Microbial infections – Viruses (viral oncogenes)
Bacteria

7. Oncogenes and cancer induction
Malignant transformation can also be happens by
viruses, its genome integrate to host DNA, oncogene
in virus induce cancer
e.g. . Rous sarcoma virus v-src gene is responsible for
cancer
Oncogenes (both viral and cellular) are derived from cellular
genes that encode various growth-controlling proteins –
The conversion of a proto-oncogene into an oncogene appears
in many cases to accompany a change in the level of expression
of a normal growth controlling protein.

8. Induction of cancer is a multi-step process
Multiple and subsequent mutations

9. look at p53

12. Malignant cancers are classified according to
embryonic origin of tissue
○Carcinomas
Endodermal or ectodermal
Skin or epithelial lining of internal organs and
glands
Colon, breast, prostate, lung
○Leukemia and lymphoma
Tumors of hematopoietic cells of bone marrow
Leukemias proliferate as single cells
Lymphomas grow as tumor masses
○Sarcomas
Mesodermal connective tissue
Bone, fat, cartilage

13. •A tumor that is not capable of indefinite growth and does
not invade the healthy surrounding tissue extensively is benign.
•A tumor that continues to grow and becomes progressively invasive
is malignant
•small clusters of cancerous cells dislodge from a tumor, invade the
blood or lymphatic vessels, and are carried to other tissues, where
they continue to proliferate. – metastasis
•carcinomas, tumors that arise from endodermal or ectodermal
tissues such as skin or the epithelial lining of internal organs and
glands
•sarcoma derived from mesodermal connective tissues such as bone
and cartilage.
•Leukemia – abnormal proliferation of WBC
•Lymphoma tumors comes on spleen and lymph node

14. TUMOR ANTIGENS TSTA & TATA
•Tumor-specific antigens are unique to tumor cells and do
not occur on normal cells in the body.
•Mutation creates new peptide- processing of it –MHCI
presents it- T cytotoxic try to kill it
•Tumor-associated antigens are not unique to tumor cells
and
occur on also in normal cells in the body Human: Chorionic
Gonadotropin (HCG), Alpha Fetoprotein (AFP), Prostate
Specific Antigen (PSA), Mucin CA 125 (glycoprotein
molecules on both normal epithelium and carcinomas),
Carcinoembryonic Antigen (CEA)

15. Category TAA Tumour
 
 
 
Unique tumour-specific
antigens
Mutant p21/ras
Immunoglobulin idiotype β-
catenin
Mutant p53 CDK4
Mutant EGFR VIII CEA
Colorectal,
pancreatic B cell
malignancy
Colorectal, breast
Pancreatic
Melanoma
Glioblastoma, lung
Colorectal
 
Overexpressed self-
antigen peptides
Muc-1 GA733/EpCam Her-
2/neu EGF Receptor
Colorectal Colorectal
Breast
Colorectal, lung,
head, and neck
Shared tumour antigensMelanoma antigen E (MAGE)
tumour-associated antigen
Melanoma
 
Viral-associated antigens
Human papilloma virus (HPV)
Hepatitis B virus (HBV)
Epstein–Barr virus (EBV)
Cervical
Hepatocellular
B cell malignancy
ExamplesExamples ofof tumour-associatedtumour-associated antigensantigens (TAAs)(TAAs) identifiedidentified inin humanshumans

16. Tumor-Specific Transplantation Antigens
(TSTAs):
Antigen that are expressed on tumor cells but
not on normal cells were called tumor-specific.
•Cancer testis antigen
•Viral antigen
•Mucin
•Oncofetal antigens
•Antigens resulting from mutational in protein
B catenin, RAS, P53,CDK4

17. •It is expressed on fetal and tumor cells not in normal
cells – E.g. oncofetal tumor antigens-like:
• Alpha-fetoprotein (AFP) found in liver cancer cells and
fetal cells as milligram and nanogram in normal cells
•
Carcinoembryonic antigen (CEA). – colorectal cancer
cells
•
The presence of these oncofetal antigens is not
diagnostic of tumors but rather serves to monitor tumor
growth.
( a patient has had surgery to remove a colorectal
carcinoma, CEA levels are monitored after surgery. An
increase in the CEA level is an indication of resumed
tumor growth.)

18. Tumor antigens-4 categories
■Antigens encoded by genes exclusively
expressed by tumors
■Antigens encoded by variant forms of
normal genes that have been altered by
mutation
■Antigens normally expressed only at certain
stages of differentiation or only by certain
differentiation lineages
■Antigens that are over expressed in
particular tumors

19. e.g:
*CD10& PSA Expressed in normal B cells & Prostate
Used as a marker for tumors arise from these cells
*human breast-cancer cells exhibit elevated
expression of the oncogene-encoded Neu protein
(HER 2), a growth factor receptor, whereas
normal adult cells express only trace amounts of
Neu protein
Oncogene proteins as tumor antigens

20. IMMUNE SURVIELLANCE THEORY – WHEN TUMOR CELLS ARISE
CELLS OF THE BODY RECOGNISE THEN & ELIMINATE
1900 , PAUL EHRLICH
•1- T cell mediated immunity
Tcyt provide effective anti tumor immunity together with class I
MHC molecules
The stimulation of TH cells activate Tcyt cells , once activated
then again co stimulation is not needed
•T H cell recognize tumor Tcyt cell destruct tumor
•CD40 on T cell amplify immune response, cytokines call
macrophages , dendritic cells
tuImmune response to Tumors

21. 2- NK cell – missing self
hypothesis –it is not MHC
restricted so it can detect &
kill tumor cells that escape
from Tcyt cells
•Antibody-Dependent Cell-
Mediate Cytotoxicity
(ADCC) is linked with NK
cells
•NK cell Activity increases
in presence of IL 2
(adoptive immunotherapy
– LAK)
Tumor surveillance by NK Cells

22. 3- Macrophage by:
•non MHC mediated
•ADCC – with antibody
•degradation of tumor is
due to lytic enzymes &
ROS
•TNF (tumor necrosis
factor)
Induces necrosis of
tumor or by thrombosis
in blood vessels
resulting in ischaematic
degradation of tumor or
direct apoptosis

23. Role of Antibodies in Tumor Immunity
In addition to their indirect beneficial role in the ADCC mechanism of
tumor killing, antibodies can also play a direct role in tumor immunity.
Antibody directed to TAA together with activation of the complement
system can kill the cancer cell by cytolytic activation of the membrane-
activation complex (MAC) cascade.
Alternatively, TAA alone or as antigen-antibody complexes can
interfere with the CTL killing of a cancer cell by blocking its activity.

24. MechanismsMechanisms ofof TumourTumour CellCell EvasionEvasion ofof thethe ImmuneImmune
ResponseResponse
1-Down regulationclass MHC I
molecules
adeno virus – inhibit
transcription of class i
mhc
herpessimplex virus
– tap inhibites

25. 2- Lack of costimulators like B.7 on apc- CD 28 on t cell
needed T cell get partial signal lead to anergic status.

26. 3-Activation of the enzyme indoleamine 2,3-dioxygenase (IDO). IDO is
an enzyme that converts tryptophan (Trp) to kynurenine (Kyn) and is
involved in tumour growth and immune suppression

27. 3-Suppession of anti tumor immune responses
•Transforming growth factor β inhibit effector
functions of NK , macrophages
•Fas ligand bind fas molecule on leukocytes –
apoptotic death of leukocytes
Preventing inflammatory response by secreting
IL 10, TGF-b- dendritic cell inactivated

28. 4- Tumor cells express
FAS L via FAS
activation lead lymph
apoptosis

29. Cancer Immunotherapy
A. Cytokine therapy.
B. Monoclonal
Antibodies.
A. Cancer vaccines.

30. B. Monoclonal antibodies: