Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

1138 Chapter 20: Cancer
cancerspecific
antigens
cancer cell
CANCER CELLS PROTECTED
BY AN IMMUNOSUPPRESSIVE
ENVIRONMENT
cancer cell
specific antigen
T cell receptor
protein that
activates
protein X
protein X
protein that
activates PD1
PD1
antibody
to protein X
antibody
to PD1
(A)
CANCER CELLS KILLED BY T CELLS
WHEN IMMUNOSUPPRESSION
REMOVED
(B)
restrained T cell
response
T cell
highly activated
T cell response
defenses include the expression on the cancer cell surface of one or more proteins
that bind to inhibitory receptors on activated T cells.
The normal immune system is subject to complex controls that keep its activity
within safe bounds and prevent autoimmunity from developing. The inhibitory
receptors that are expressed on the surface of activated T cells have an important
normal function: they control the immune response by down-regulating the T
cell response under appropriate circumstances. But in the context of a tumor, the
down-regulation is inappropriate, because it prevents the organism from killing
MBOC6 n20.600/20.45
the cancer cells that are threatening its survival.
In its attack on infectious organisms, the natural immune system usually eliminates
every last trace of infection and maintains this immunity in the long term.
The challenge is to find ways of recruiting the immune system to attack cancers
with similar efficiency and specificity, hunting the cancer cells down by virtue of
the tumor-specific antigens that they express. With this aim, a new type of anticancer
therapy focuses on overcoming the immunosuppressive environment in
a tumor through the use of specific antibodies that prevent the tumor cells from
engaging with the inhibitory receptors on T cells. As illustrated in Figure 20–45A,
blocking the action of the immune suppressors with such treatments should
unleash an immune attack on the cancer cells. Importantly, multiple antigens
are recognized as foreign; thus, the cancer cells cannot escape through the mutational
loss of a single antigen, making it difficult for the tumor to escape from the
T cell attack.
This is a potentially dangerous strategy. If one provokes the immune system to
recognize the cancer cells as targets for destruction, there is a risk of autoimmune
side effects with dire consequences for normal tissues of the body, since the cancer
cells and the normal cells are close cousins and share most of their molecular
features. Nevertheless, several recent successes seem to hold great promise for
the future.
One of the many molecules involved in keeping the activity of the normal
immune system within safe bounds is a protein called CTLA4 (cytotoxic T-lymphocyte-associated
protein 4), which functions as an inhibitory receptor on the
surface of T cells. If the function of CTLA4 is blocked, the T cells become more
reactive and may mount an attack on cells that they would otherwise leave
in peace. In particular, the T cells may attack tumor cells that are recognizably
abnormal but whose presence was previously tolerated. With this in mind, cancer
immunologists developed a monoclonal antibody, called ipilimumab, that binds
to CTLA4 and blocks its action. Injected repeatedly into patients with metastatic
melanoma, this antibody increases their median lifespan by several months and,
in one large trial, enabled as many as a quarter of them to survive for five years
Figure 20–45 Therapies designed
to remove the immunosuppressive
microenvironment in tumors. (A) The
cells in tumors will produce many mutant
proteins. As described in Chapter 24,
peptides from these proteins will be
displayed on MHC complexes on the
tumor-cell surface and would normally
activate a T cell response that destroys
the tumor (see Figure 24–42). However, as
schematically illustrated, during the course
of tumor progression, the cancer cells have
evolved immunosuppressive mechanisms
that protect them from such killing. (B) The
cells in tumors often protect themselves
from immune attack by expressing
proteins on their surface that bind to and
thereby activate the inhibitory receptors
on T cells. As indicated, this makes the
tumor susceptible to specific antibody
therapies. In this diagram, two such
inhibitory receptors are shown, PD1 and a
hypothetical protein X. Different tumors are
thought to protect themselves by activating
different members of a large set of T cell
inhibitory receptors, some of which are not
yet well characterized.