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