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Lecture Notes - Tumor Immunology - week 2
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  • Course
  • Tumor Immunology
  • Institution
  • Vrije Universiteit Amsterdam (VU)
  • Book
  • Janeway\'s Immunobiology

Lectures included: immune escape mechanism, PD-1/PD-L1 interference, TLR-directed therapy, DC immunotherapy, checkpoint inhibition, DNA & RNA tumor vaccine, NKT cells & gamma delta T cells, immunoscore

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  • January 9, 2020
  • 41
  • 2018/2019
  • Class notes
  • Unknown
  • All classes

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  • tumor immunology
  • mandatory courses master oncology vu amsterdam

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Module 2: Tumor Immunology (Week 2)

LECTURE 11: IMMUNE ESCAPE MECHANISMS Monday, 8/10/2018

Lessons from HPV-related cervical cancer:

3rd most common cancer type in women worldwide

Cervical cancer: HPV infects basal layer  replicates  spread of HPV
after top-most cell layer dies off (spreading requires episomal structures
unattached to the genome for mobilization)

Not all HPV-infected cells grow into malignant cluster (effective
immune clearance); only 10 subtypes are considered carcinogenic

Preventive vaccination: mainly for HPV-16 & HPV-18  peptides elicit
immune response against HPV-infected cells & induce immune clearance
(47% remission rate in vulvar intraepithelial neoplasia cases)

Early stage has high 5-year survival rate (80%), but low survival of
advanced/metastatic cervical cancer

Most dangerous viral protein: E6 & E7

Able to escape immune regulation by downregulation of HLA class
1/MIC A and switching to non-classical HLA


Immune response to cancer cells

a. Priming adaptive response: DC
vaccine, cancer-antigen-based
vaccine
b. Effector adaptive response: T-cell
adoptive transfer, checkpoint
inhibition

Adoptive transfer: isolate T cell from
patient  activation/enhancement ex vivo
 reintroduce to patient

CP inhibition: loosen brakes for CD8+ T cell
proliferation




Circumventing immune elimination by inducing immunosuppression: release of inhibitory molecules (TGF beta,
IL-10, VEGF, IDO, PGE-2, etc), upregulation of T cell inhibitory receptors (PD-1, CTLA-4, TIM-3, etc), loss of T
cell activating receptors (HLA), recruitment of suppressive immune cells (Treg & MDSC)

, Module 2: Tumor Immunology (Week 2)

Cascade of immune activation




Antigen taken up by APC  presented by MHC II to Th cell (also releasing co-stimulatory cytokines)  Th
activation  Th memory cells  releasing IL-2  affect production of cytotoxic T cell

T cell can also be activated by presentation of antigen by MHC I  direct cytotoxicity to altered cell

Immune escape mechanism

Increasing levels of Treg (marker: FOXP3), damaged HLA (no killing by NK cell), lack of MHC presentation in
APC  no activation of T cells, loss of MHC/MIC A  no detection by cytotoxic T cell

Means of immune evasion:

a. Cytokines production
b. T cell inhibitory receptors
c. Loss of activating receptor (no HLA)
 T cells do not recognize tumor
cells as foreign & no cytotoxicity
Backup mechanism: low HLA
expression on cell surface detected
by NK cells  cell destruction
Wrong HLA expression (like in most
tumor) = NK cell does not sense as
target, no cell destruction
d. High amount of suppressive cells (T
reg, MDSC)

, Module 2: Tumor Immunology (Week 2)

HLA Class I

HLA: classical (HLA-A, etc), non-classical (HLA-G, HLA-E); HLA-A & HLA-G have cross-reactivity to HCA-2
marker

Mechanism of HLA activity

Oligopeptide (e.g. TAA)  transported into
ER by TAP  form complex with other
proteins  presentation to HLA + surface
migration through Golgi complex  T cell
recognition + response

HLA complex require stabilization by several
molecules (calnexin, calreticulin, tapasin, etc)
in order to be able to bind to the antigen &
carry the antigen to the cell surface




Functional HLA: stable, peptide-bound structure  has 2 A alleles, 2 B alleles, 2 C alleles; induction of T cell
cytotoxicity requires all alleles to be intact, if one allele is lost/wrong: reduced T cell recognition & no
cytotoxicity

HLA alterations in cancer
In cancer cells: altered HLA
expression  total loss,
loci/alleleic loss, haplotype loss,
compound phenotype  T cell
can’t be activated

In cervical cancer: 50% cases
express reduced HLA, 20% no HLA
expression

In cervical Ca cases with weak
HLA expression (IHC staining):
worse prognosis than no HLA
expression

Normal cervix: MIC A(+), HLA-G(-)

, Module 2: Tumor Immunology (Week 2)

Genetic aberrations causing HLA alterations (examination method: allele-specific FACS):

a. Beta-2m loss: total loss of HLA

b. LOH: haplotype loss of HLA

c. Certain genetic mutations: alleleic loss of HLA

HLA analysis




HLA alterations in cervical cancer

Cervical cancer express MIC A & non-classical HLA-E: can bind to NKG2A receptor on NK cell  activation or
inhibition (depending on the skewing of activating/inhibiting signals); normally functions as a brake to immune
reaction, activating effects depend on the presence of other T cell receptors

More aberrations of HLA expression in metastatic tumor (addition of other classic HLA loss/HLA-B & HLA-C)

Escape mechanisms = escaping T cell detection (HLA-A loss) + escaping NK cell detection (HLA-G upregulation)

Chemotactic cytokines by cervical cancer cells

CCL2: attract immune cells to tumor site  more CCL2 = higher T cell infiltration

Increased CCL2 production by tumor cells  more leaky vessels  extravasation of immune cells  homing to
tumor site; however, CCL2 expression by tumor cells is sometimes followed by differentiation of macrophages
into TAM (more suppressive, marker: CD68)

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