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
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)
Alle Vorteile der Zusammenfassungen von Stuvia auf einen Blick:
Garantiert gute Qualität durch Reviews
Stuvia Verkäufer haben mehr als 700.000 Zusammenfassungen beurteilt. Deshalb weißt du dass du das beste Dokument kaufst.
Schnell und einfach kaufen
Man bezahlt schnell und einfach mit iDeal, Kreditkarte oder Stuvia-Kredit für die Zusammenfassungen. Man braucht keine Mitgliedschaft.
Konzentration auf den Kern der Sache
Deine Mitstudenten schreiben die Zusammenfassungen. Deshalb enthalten die Zusammenfassungen immer aktuelle, zuverlässige und up-to-date Informationen. Damit kommst du schnell zum Kern der Sache.
Häufig gestellte Fragen
Was bekomme ich, wenn ich dieses Dokument kaufe?
Du erhältst eine PDF-Datei, die sofort nach dem Kauf verfügbar ist. Das gekaufte Dokument ist jederzeit, überall und unbegrenzt über dein Profil zugänglich.
Zufriedenheitsgarantie: Wie funktioniert das?
Unsere Zufriedenheitsgarantie sorgt dafür, dass du immer eine Lernunterlage findest, die zu dir passt. Du füllst ein Formular aus und unser Kundendienstteam kümmert sich um den Rest.
Wem kaufe ich diese Zusammenfassung ab?
Stuvia ist ein Marktplatz, du kaufst dieses Dokument also nicht von uns, sondern vom Verkäufer oddsters. Stuvia erleichtert die Zahlung an den Verkäufer.
Werde ich an ein Abonnement gebunden sein?
Nein, du kaufst diese Zusammenfassung nur für 3,99 €. Du bist nach deinem Kauf an nichts gebunden.
