ANTITUMOR EFFECTOR
MECHANISMS
&
IMMUNE
SURVEILLANCE
Imelda Salas Lorenzo
ANTITUMOR EFFECTOR MECHANISMS
Although both cell-mediated and humoral immunity have been
demonstrated to have antitumor activity, the principal
mechanism of tumor immunity is killing of tumor cells by
CD8+CTLs
Cellular effectors that mediate immunity
Cytotoxic T Lymphocytes (CTL)
the antitumor effect of cytotoxic T cells reacting against
tumor antrigens is well established in experimentally
induced tumors
human, CTLs play a protective role against virus-
associated neoplasms and have been demonstrated in
the blood and tumor infiltrates of cancer patients
transfection of cytokine genes into tumor-infiltrating
lymphocytes to potentiate their antitumor effects
Natural Killer Cells (NK)
lymphocytes that are capable of destroying tumor cells
w/out prior sensitation
many tumors down-regulate expression of class I MHC
molecules as a way of invading immunity
particularly effective against cells w/ reduced MHC
expression
after activation w/ IL-2, NK cells can lyse a wide
variety of human tumors in vitro. Adoptive
immunotherapy w/ in vitro expanded and activated
human NK cells has met w/ limited success
importance in defense against most spontaneously
arising tumors remains unclear
Macrophages
activated macrophages are effective at killing tumor
cells in vitro T cells and NK cells may collaborate w/
macrophages in antitumor reactivity because
interferon- y
(IFN- y) is a potent activator of macrophages
kill tumors by mechanisms similar to those used to kill
microbes
ex. Production of reactive O metabolites
Antibodies
kill tumors cells by activating complement or antibody-
dependent cell-mediated cytotoxity, in w/c Fc receptor-
bearing macrophages or NK cells mediate the killing
the ability of antibodies to eliminate tumor cells have
been demonstrated in vitro and there is evidence for
effective humoral immunity against tumors
IMMUNE SURVEILLANCE
strongest argument for the existence of immune
surveillance is the increased frequency of cancers in
immunodeficient hosts
5% of persons w/ congenital immunodefficiencies develop
cancers, about 200 times the prevalence in
immunocompetent individuals
Immunosuppressed transplant recipients and patient w/
AIDS also have an increased incidence of malignancies
Most of these Neoplasms are lymphomas, often
immunoblastic B-cell lymphomas
X-linked recessive immunodeficiency
XLP (X-linked lymphoproliferative syndrome)
disorder caused by mutations in the gene encoding
an adapter protein (SAP), w/c participates in
lymphocyte signalling pathways
boys affected by XLP develop an EBV infection, it
does not take the usual self-limited form of
infectious mononucleosis but it evolves into a
severe form of infectious mononucleosis
25% of XLP patients develop malignant B-cell
lymphomas
most cancer occur in person who do not suffer from
any immunodeficiency
tumor cells must develop mechanisms to escape or evade the
immune system in immunocompetent hosts
Figure 1. Mechanism by w/c tumors evade the immune system
Selective outgrowth of antigen-negative variants
immunogenic subclones may be eliminated
Loss or reduced expression of MHC molecules
tumor cells may fail to express normal levels of HLA class I
molecules, thereby attack by cytotoxic T cells. Such cells
may trigger NK cells
Lack of Castimulation
sensitization of T cells requires two signals, one by peptide
presented by MHC molecules and by the costimulatory
molecules
although tumor cells may express peptide antigens w/
class I molecules, they do not express costimulatory
molecules
this not only prevents sensitization, but also may render T
cells anergic or cause them to undergo apoptosis
to bypass this problem, attempts are being made to immunize
patients w/ autologous tumors cells that have been transfected
w/ the gene for the costimulatory molecule B7-1
autologous dentric cells expanded in vitro and pulsed w/ tumor
antigens (MAGE -1) are infused into cancer patients. Bec.
Dentric cells express high levels of costimulatory molecules, it
is expected that such immnization will stimulate antitumor T
cells
Immunosuppression
oncogenic agents ( chemicals and ionizing ions) suppress host
immune resposes
tumors or tumor products may also be immunosuppressive
ex. TGF-b, secreted by many tumors, is a potent
immonusuppressant
immune response induced by the tumor (activation of
regulatory T cells) may itself inhibit tumor immunity
Antigen Masking
cell-surface antigens of tumors may be hidden from the
immune system by glycocalyx molecules (acid-containing
mucopolysaccharides)
maybe a consequence of the fact that cells often express
mare of these glycocalyx molecules than normal cells do
Apoptosis of cytotoxic T cells
melanomas and hepacellular carcinomas express Fas ligand
these tumors kill Fas-expressing T lymphocytes that come
in contact w/ them, thus eliminating tumor-specific T cells
it is worth mentioning that although much of the focus in the field
of tumor immunity has been on the mechanisms by w/c the host
immune system defends against tumor, there is recent evidence
that the immune system may promote the growth of tumors
it is possible that activated lymphocytes and macrophages
produce growth factors for tumor cells or enzymes, such as MMPs,
that enhance tumor invasion
harnessing the protective actions of the immune system and
abolishing to increase tumor growth is obviously an important
goal of immunologists and oncologists
THANK YOU!
HAVE A NICE DAY
