Lecture_2_Medical_Biotechnology copy.pdf

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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


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Figure 2.1: Potential anti-cancer immune effectors


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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


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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


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different MHC alleles bind different antigen-derived peptides

diversity in antigen presentation

Figure 2.4: MHC allelic variations occur in the peptide-binding pocket


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Figure 2.5: Class I restricted recognition: generation of killer T cells


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Figure 2.6: Class I restricted recognition: impaired generation of killer T cells

Tumor growth factor- (TGF-)

Interleukin-10 (IL-10)


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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


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Figure 2.8: Adoptive transfer of tumor-infiltrating lymphocytes (TILs)


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Figure 2.9: Identification of mutagen-induced TS(T)As(tumor specific transplantation antigens)


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Figure 2.10: Molecular identification of mutagen-induced TSAs


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Figure 2.11: Identification of naturally occurring TSA (murine)


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Figure 2.12: Identification of naturally occurring TSA (CTL screening)


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Figure 2.13: CTL screening of TSA - continuation


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Figure 2.14: Class II restricted recognition: generation of antibodies


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Figure 2.15: Identification of naturally occurring TSA (antibody screening)

SEREX: serological analysis of recombinant cDNA expression libraries of human tumors with autologous serum


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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


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Figure 2.17: Class I restricted recognition: generation of killer T cells


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Figure 2.18: Class I restricted recognition: bypassing signal 2


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Figure 2.19: Anti-cancer vaccination using dendritic cells


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Figure 2.20: Pathways of antigen processing/presentation


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Figure 2.21: Role of LMP/TAP in antigen processing

Deficiencies in antigen processing:

tumor escape

tools for tumor specific peptide screening

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