it , ImmunoTechnology

2. Types of tumor antigens recognized by T cells
Immune mechanisms of tumor rejection
How tumors evade immune responses?
Novel therapeutic approaches (immunotherapies)

3. Types of Tumor antigens
Tumor-associatedantigens
(TAAs)
Tumor-specificantigens
(TSAs)

4. T
umor-associated
antigens
•expressed also on normal cells .
•normal cellular constituents but aberrant or
dysregulated in tumors .
T
umor-specific
antigens
•expressed on tumor cells but not on normal
cells .
•individually unique or shared.

5. Tumor reactive CTLs lines fromcancer patients
Relevant peptide antigens .
CD4Tcel lines fortumor antigens .
 SEREX(serologicalanalysisofrecombinantcDNAexpression)
humoralimmuneresponsesintumorpatientsUsingantibodiespresentpatient’sserum.

7. 1
- Abnormally expressed but unm
utated cellular
proteins :
• Normal cellular proteins that are either
overexpressed or whose expression is normally
limited to particular tissues or stages of
development but is dysregulated in tumor cells.
• This aberrant expression may be enough to
elicit such responses.
• e.g. Self protein that are expressed only in
embryonic tissues may not induce tolerance in
adults .

8. 2-Productsofm
utatedselfgenes:
• Intrinsic genomic instability of many cancers .
• Tumor antigens may be produced by randomly
mutated genes whose products are not related
to the malignant phenotype .
• Class I MHC pathway
• Wide variety of genes may be mutated in tumor
cells.

9. 3-O
ncogenesandmutatedtumor suppressor genes:
• Differ from normal cellular proteins .
• Class I MHC pathway
• Mutated Ras , Bcr/Abl fusion protein are two
examples of oncogenes.
• Mutated p53 is an example of mutated tumor
expressed gene .

10. 4-Antigens ofO
ncogenicviruses:
• The products of oncogenic virus: function as
tumor antigens and elicit specific T cell
responses
• Virus-encoded protein antigens are found in the
nucleus, cytoplasm or plasmamembrnare of the
tumor cells.
• most immunogenic tumor antigens.
• shared by all tumors induced by the same type
of virus

11. 4-Antigens ofO
ncogenicviruses:
DNA viruses RNA viruses

12. 4-Antigens ofO
ncogenicviruses:
RNA viruses
• EBV: Bcell lymphomas, nasopharyngeal
carcinoma
• HPV : cervical carcinoma
• Popovaviruse and adenovirus
• HPV vaccine for cervical cancer in women
• Vaccination against HepatitisBvirus

13. 4-Antigens ofO
ncogenicviruses:
• Human Tcell lymphotropic virus 1 (HTLV-1)
• Adult Tcell leukemia/lymphoma (ATL)
DNA viruses

14. 5-oncofetalantigens:
• Proteins expressed at high levels in cancer cells and in normal developing fetal but not
adult tissues
• Silent during development, derepressed with malignant transformation
• Increased in tissues and in the circulation in various inflammatory conditions
• Markers for tumor diagnosis
• Small quantities even in normal tissues .
α-fetoprotein (AFP)
Carcinoembryonic antigen (CEA:CD66)
Oncofetal antigens

15. 6-Tissue-specificdifferentiationantigens :
• Tumors may express molecules that are present only on the normal cells of origin and not
on cells from other tissues
• Melanoma antigens : targets of CTLs (Tyrosinase)
• Lymphomas :CD10 and CD20

17. Tumors infiltrated with lymphocytes show less chance to survive than coated
tumors .
Lymphocytes proliferation in lymph nodes in some tumors point to an immune
response
tumors of those who take immune suppressors
Regression of some tumors spontaneously “lymphoma ,mylanoma”
High ratio of tumors of neonatals and olders who have weak immune reactions

19. studies have focused on the antitumor response of CTLs
because most tumors express class I Major
Histocompatibility Complex (MHC) antigens and not
MHC class II antigens.
Antitumor immunity
results from both:

20. Macrophage/Dendritic cell attack or antigen
presentation
CD8 cell-mediated cytotoxicity
Antibody dependent cell mediated cytotoxicity
(ADCC)
Natural killer cells

25.  It Does not recognize tumor cell via antigen
specific cell surface receptor, but rather
through receptors that recognize loss of
expression of MHC I molecules, therefore
detect “missing self” common in cancer.
 NK cells may also recognize specific proteins
up-regulated and presented by cancer cells.
Studies have indicated that cells in distress,
including tumor cells, tend to express Rae1
and H60 ligands, which are not expressed in
normal cells. The Rea1 andH60 ligands are
recognized by the NKG2D receptor, which is
regularly expressed by NK cells, activated
CTLs and activated macrophages
N K
cell
Target cell
(infected or
cancerous)
Perforin and
enzymes
killer
activating
receptor

26. cell recognizes a
Once an NK
cancer cell, it secretes the pore
forming granule perforin into the
region of the immunological
synapse, thus causing target cells
to lyse
NK cells activate dendritic cells by
producing IFN-γ (thus enhancing
tumor immunogenicity), and also
by providing DC with increased
access to tumor antigens by killing
activity.

28. Immune responses often fail to check tumor growth, because these responses
are ineffective or because tumors evolve to evade immune attack
The immune system faces a daunting challenge if it has to be effective against malignant
tumors because:
Immune responses must kill all tumor cells and tumors
grow rapidly. Often, the growth simply outstrips immune
defenses.
Immune responses against tumors may be weak because
many tumor antigens are weakly immunogenic, perhaps
because they differ only slightly from self-antigens.
Growing tumors also develop mechanisms for evading
immune responses.

30. Evasion of Immune Responses by Tumors:
 Loss of T cell recognition:
 Antigen loss variants
 Loss of TAPs and other molecules involved in antigen processing
 Stop expressing class ∣ MHC molecules

31. Evasion of Immune Responses by Tumors:
Explanations for why tumor cells that have lost HLA
class I are not destroyed by NK cells ?
loss or down-regulation of NKG2D ligands expression
lack of stimulatory cytokines and secretion of
immunosuppressant cytokines
producing the matrix metalloproteinase 9, which results
in ICAM-1 shedding and resistance to NK cell killing

32.  Tumor antigens may be inaccessible to the immune system:
 Antigen masking:
tumor cells express more of glycocalyx molecules than normal cells do.
 The cell surface antigens :
 hidden from the immune system by glycocalyx molecules (sialic acid-containing
mucopolysaccharides)
Glycocalyx molecule
(sialic acid-
containing
mucopolysaccharide
s)
Evasion of Immune Responses by Tumors:

33. Tumor may engage molecules that inhibit immune
response:
 Involvement of PD-L1 , CTLA-4
Secreted products of tumor cells may suppress anti-
tumor immune response:
 TGF-β,secreted in large quantities by many tumors that Inhibits the proliferation
and effector functions of lymphocytes and macrophages
Evasion of Immune Responses by Tumors:

34. Evasion of Immune Responses by Tumors:
Tumor-associated macrophages (TAMs):

35. Evasion of Immune Responses by Tumors:
 Regulatory T cells: may suppress T cell responses to
tumors:
A population of T cells that regulate the activation or effector
functions of other T cells and may be necessary to maintain
tolerance to self antigens.
Regulatory T cells express 𝐂𝐃𝟒+and CD25
Depletion of regulatory T cells in tumor-bearing mouse enhances
anti-tumor immunity and reduces tumor growth

36.  Regulatory T cells:

37.  the Fas counter attack :

39. is the use of immune system to reject cancer .
What about Chemotherapy?

40. Types of Cancer
Immunotherapy

41. Naked mAbs
Conjugated mAbs :
Radiolabelled
Chemolabelled
Immunotoxin

43. Types of Cancer
Immunotherapy

45. Types of Cancer
Immunotherapy

46. • Therapeutic cancer vaccines trigger the immune system to
recognize and attack certain markers, or antigens, present on or in
cancer cells .
• Unlike traditional vaccines, which help to prevent disease,
therapeutic cancer vaccines treat disease that is already there .
• Cancer vaccines often require additional substances called
adjuvants for optimal effectiveness .

47. Cancer Vaccines :
 Antigen vaccines
 Dendritic cell vaccines
 DNA vaccines .

52. Types of Cancer
Immunotherapy

54. Types of Cancer
Immunotherapy

55. In late 1800’s Dr William Coely first noted that getting
an infection after surgery seemed to help some
cancer patients .
He began treating cancer patient’s by infecting them
with certain kinds of bacteria , which came to be
known as Coely toxins .

56. • Oncolytic viruses are viruses that directly kill (“lyse”) cancer
cells and can also activate cells of the immune system, such as
dendritic cells and T cells, to target and eliminate cancer
throughout the body .
• Sometimes, Oncolytic viruses are genetically modified to
produce immune-stimulating chemicals, or to make them more
specific for cancer cells .
• Oncolytic virus immunotherapies are often combined with other
types of cancer immunotherapies, including therapeutic cancer
vaccines and mAb therapy

59. Types of Cancer
Immunotherapy

60. Cytokines are messenger molecules that help control
the growth and activity of immune system cells
interleukins (IL) help immune cells grow and divide
more quickly
interferons (IFN) boost the ability of certain immune
cells to attack cancer cells