Upload
manondemulder
View
228
Download
0
Embed Size (px)
Citation preview
7/30/2019 Lecture_2_Medical_Biotechnology copy.pdf
1/22
Lecture 2: Potential anti-cancer immune effectors part 1: cytotoxic T cells (CTLs)
Overview (i) Potential anti-cancer immune effectors
(ii) The Major Histocompatibility Complex
Fig 2.1
Fig 2.2-2.4
Generation of cancer cell-specific CTLs
(i) Pathways and tumor-induced suppression Fig 2.5-2.7
(ii) The TIL-cell therapy Fig 2.8
Identification of tumor-specific antigens (TSAs) via CTLs
(i) Mutagen-induced TSAs Fig 2.9-2.10
(ii) Naturally occurring TSAs (murine) Fig 2.11
(iii) Naturally occurring TSAs (human) Fig 2.12-2.13
Identification of TSAs via antibodies (Abs)
(i) Generation of cancer cell-specific Abs Fig 2.14
(ii) Ab screening of TSAs Fig 2.15
Types of TSAs Fig 2.16
Optimal generation of TSA-specific CTLs
(i) Costimulatory signals Fig 2.17-2.18
(ii) Anti-cancer vaccination using Dendritic Cells Fig 2.19
(iii) Antigen-processing/presentation defects Fig 2.20-2.21
7/30/2019 Lecture_2_Medical_Biotechnology copy.pdf
2/22
Figure 2.1: Potential anti-cancer immune effectors
7/30/2019 Lecture_2_Medical_Biotechnology copy.pdf
3/22
A group of tightly-linked genes encoding proteins related to immune recognition
Polygenic (several different MHC genes) with codominant expression Human MHC region is called HLA
Murine MHC region is called H-2
Three main regions called I, II, and III:
Region I encodes MHC class I
molecule heavy chain: K, D, & L in mouse
A, B, & C in human
Region II encodes MHC class IImolecule and chain:
I-A and I-E in mouse
DP, DR, & DQ in human
Region III encodes other immune-related secreted molecules
Complement (C) proteins,TNFa/b
Figure 2.2: The Major Histocompatibility complex: gene structure
7/30/2019 Lecture_2_Medical_Biotechnology copy.pdf
4/22
MHC class HLAlocus
Number ofallotypes
MHC class I
A 218
B 439
C 96
MHC class II
DP 1
DP 1
12
88
DQ 1
DQ 1
17
42
DR
DR 1DR 3
DR 4
DR 5
2
26930
7
12
Highly polymorphic (many different alleles)
Haplotype = a particular combination ofHLA alleles at each of the loci (1 inheritedfrom father; one from mother)
Chance of finding a fully HLA-matcheddoner: on average 1/30 000
In mice: inbred mouse strains:
each mouse of the strain has the same
H-2 alleles
Figure 2.3: The Major Histocompatibility complex: polymorphism
7/30/2019 Lecture_2_Medical_Biotechnology copy.pdf
5/22
different MHC alleles bind different antigen-derived peptides
diversity in antigen presentation
Figure 2.4: MHC allelic variations occur in the peptide-binding pocket
7/30/2019 Lecture_2_Medical_Biotechnology copy.pdf
6/22
Figure 2.5: Class I restricted recognition: generation of killer T cells
7/30/2019 Lecture_2_Medical_Biotechnology copy.pdf
7/22
Figure 2.6: Class I restricted recognition: impaired generation of killer T cells
Tumor growth factor- (TGF-)
Interleukin-10 (IL-10)
7/30/2019 Lecture_2_Medical_Biotechnology copy.pdf
8/22
Figure 2.7: Class I restricted recognition: impaired activity of killer T cells
Indoleamine 2,3-dioxygenase (IDO) -> tryptophane catabolism
(Arginase/iNOS -> arginine catabolism)
AMINO ACID CATABOLISM
Remarks: Involvement of tumor stromal cells
Natural role in pathogen defense & in immune tolerance processes
7/30/2019 Lecture_2_Medical_Biotechnology copy.pdf
9/22
Figure 2.8: Adoptive transfer of tumor-infiltrating lymphocytes (TILs)
7/30/2019 Lecture_2_Medical_Biotechnology copy.pdf
10/22
Figure 2.9: Identification of mutagen-induced TS(T)As(tumor specific transplantation antigens)
7/30/2019 Lecture_2_Medical_Biotechnology copy.pdf
11/22
Figure 2.10: Molecular identification of mutagen-induced TSAs
7/30/2019 Lecture_2_Medical_Biotechnology copy.pdf
12/22
Figure 2.11: Identification of naturally occurring TSA (murine)
7/30/2019 Lecture_2_Medical_Biotechnology copy.pdf
13/22
Figure 2.12: Identification of naturally occurring TSA (CTL screening)
7/30/2019 Lecture_2_Medical_Biotechnology copy.pdf
14/22
Figure 2.13: CTL screening of TSA - continuation
7/30/2019 Lecture_2_Medical_Biotechnology copy.pdf
15/22
Figure 2.14: Class II restricted recognition: generation of antibodies
7/30/2019 Lecture_2_Medical_Biotechnology copy.pdf
16/22
Figure 2.15: Identification of naturally occurring TSA (antibody screening)
SEREX: serological analysis of recombinant cDNA expression libraries of human tumors with autologous serum
7/30/2019 Lecture_2_Medical_Biotechnology copy.pdf
17/22
Cancer/testis antigens
MAGE family
NY-ESO-1
Differentiation antigens
E.g. Melan-A/MART-1, tyrosinase in melanoma
Mutational antigens
E.g. mutated p53
Viral antigens
E.g. EBV, HPV antigens
Overexpressed/amplified antigens
E.g. HER-2/neu
Figure 2.16: Types of tumor specific antigens
7/30/2019 Lecture_2_Medical_Biotechnology copy.pdf
18/22
Figure 2.17: Class I restricted recognition: generation of killer T cells
7/30/2019 Lecture_2_Medical_Biotechnology copy.pdf
19/22
Figure 2.18: Class I restricted recognition: bypassing signal 2
7/30/2019 Lecture_2_Medical_Biotechnology copy.pdf
20/22
Figure 2.19: Anti-cancer vaccination using dendritic cells
7/30/2019 Lecture_2_Medical_Biotechnology copy.pdf
21/22
Figure 2.20: Pathways of antigen processing/presentation
7/30/2019 Lecture_2_Medical_Biotechnology copy.pdf
22/22
Figure 2.21: Role of LMP/TAP in antigen processing
Deficiencies in antigen processing:
tumor escape
tools for tumor specific peptide screening