Report on cancer immunology

1. ｱﾊﾞｵﾗﾘｰﾈﾙﾋﾞﾙﾊﾞｵ February 4, 2010
Infection Immunology おがわ先生
Cancer Immunology & Transplantation Immunology
According to Wikipedia, cancer immunology is the study of interactions between the
immune system and cancer cells (also called tumors or malignancies). It is also a
growing field of research that aims to discover innovative cancer immunotherapies to
treat and retard progression of this disease. The immune response, including the
recognition of cancer-specific antigens, is of particular interest in this field.
Knowledge accumulated in the field drove (and is still driving) the development of
new vaccines and antibody therapies.
For instance in 2007, Ohtani published a paper finding a tumor infiltrating
lymphocytes to be quite significant in human colorectal cancer.1 The host was given
a better chance of surviving if the cancer tissue showed infiltration of inflammatory
cells (in particular lymphocytic reactions). The results yielded suggested some
extent of anti-tumor immunity that is present in colorectal cancers in humans.
Over the past ten (10) years, there has been a notable progress and an accumulation
of scientific evidence for the concept of cancer immune surveillance and immune
editing based on: (1) protection against development of spontaneous and chemically-
induced tumors in animal systems; and (2) identification of targets for immune
recognition of human cancer. In 1999, a rat with immunity to cancer was discovered
by Dr. Zheng Cui.
Through the lecture conducted and reading materials in cancer immunology, I have
learned a lot of things. First, tumors express antigens that are recognized by the
immune system, but most tumors are weakly immunogenic and immune responses
often fail to prevent the growth of tumors. The immune system can be stimulated to
effectively kill tumors.2
Secondly, tumor antigens recognized by CTLs are the principal inducers of and
targets for antitumor immunity. These antigens include mutants of oncogenes and
other cellular proteins, normal proteins (whose expression is dysregulated or
increased in tumors), and products of oncogenic viruses.
Thirdly, antibodies specific for tumor cells recognize antigens that are used for
diagnosis and are potential targets for antibody therapy. These antigens include
oncofetal antigens, which are expressed normally during fetal life and whose
expression is dysregulated in some tumors; altered surface glycoproteins and
glycolipids; and molecules that are normally expressed on the cells from which the
tumors arise and are thus differentiation antigens for particular cell types.
Fourthly, immune responses that are capable of killing tumor cells consist of CTLs,
NK cells, and activated macrophages. The role of these immune effector
mechanisms in protecting individuals from tumors is not well-defined.
1
H. Ohtani, (2007). Focus on TILs: Prognostic significance of tumor infiltrating lymphocytes in human colorectal
cancer. Cancer Immunity 7: 4.
2 th
Abul K. Abbas, Cellular and Molecular Immunology (6 Edition), pp. 397-416.
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2. Fifthly, tumors evade immune responses by several mechanisms, including down-
regulating the expression of MHC molecules, selecting cells that do not express
tumor antigens, producing immunosuppressive substances, and inducing tolerance
to tumor antigens.
And lastly, immunotherapy for tumors is designed to augment active immune
responses against these tumors or to administer tumor-specific immune effectors to
patients. Immune responses may be actively enhanced by vaccination with tumor
cells or antigens, administration of tumors modified to express high levels of co-
stimulators or cytokines that stimulate T cell proliferation and differentiation, and
systemic administration of cytokines. Anti-tumor immunity may also be enhanced by
blocking inhibitory pathways of immuno-regulation. Approaches for passive
immunotherapy include the administration of anti-tumor antibodies, antibodies
conjugated with toxic drugs (immunotoxins), and tumor-reactive T cells and NK cells
isolated from patients and expanded by culture with growth factors.
Meanwhile, transplantation immunology is defined as a general term for the complex
phenomena involved in allo- and xenograft rejection by a host and graft vs. host
reaction.3 Although the reactions involved in transplantation immunology are
primarily thymus-dependent phenomena of cellular immunity, humoral factors also
play a part in late rejection.
In transplantation immunology, I came to know some general principles through the
lecture conducted and by reading related materials (in the Internet and some books).4
First, transplantation of tissues from one individual to a genetically non-identical
recipient leads to a specific immune response called rejection that can destroy the
graft. The major molecular targets in transplant rejection are allogeneic class I and
class II MHC molecules.
Secondly, many different, normally present T cell clones specific for different foreign
peptides plus self-MHC molecules may cross-react with an individual allogeneic MHC
molecule. This high frequency of T cells capable of directly recognizing allogeneic
MHC molecules explains why the response to alloantigens is much stronger than the
response to conventional foreign antigens.
Thirdly, allogeneic MHC molecules may be represented on donor APCs to recipient T
cells (the direct pathway), or the alloantigens may be picked-up by lymphoid organs
and be processed and presented to T cells as peptides associated with self MHC
molecules (the indirect pathway). Graft rejection is mediated by T cells, including
CTLs that kill graft cells and helper T cells that cause DTH reactions, and by
antibodies.
Fourthly, several effector mechanisms cause rejection of solid organ grafts, and each
mechanism may lead to a histologically characteristic reaction. Pre-existing
antibodies cause hyper acute rejection characterized by thrombosis of graft vessels.
Alloreactive T cells and antibodies produced in response to the graft cause blood
vessel wall damage and parenchymal cell death, called acute rejection. Chronic
rejection is characterized by fibrosis and vascular abnormalities (accelerated
arteriosclerosis), which may represent a chronic DTH reaction in the walls of arteries.
3
http://www.mondofacto.com/facts/dictionary?transplantation+immunology
4 th
Abul K. Abbas, Cellular and Molecular Immunology (6 Edition), pp. 375-395.
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3. Fifthly, rejection may be prevented or treated by immuno-suppression of the host and
by minimizing the immunogenicity of the graft (by limiting MHC allelic differences).
Most immunosuppresion is directed at T cell responses and entails the use of
cytotoxic drugs, specific immunosuppressive agents, or anti-T cell antibodies. The
most widely used immunosuppressive agent is cyclosporine, which blocks T cell
cytokine synthesis. Immuno-suppression is often combined with anti-inflammatory
drugs such as corticosteroids that inhibit cytokine synthesis by macrophages.
Sixthly, patients receiving solid organ transplants may become immunodeficient
because of their therapy and are susceptible to viral infections and virus-related
malignant tumors.
Seventhly, xenogeneic transplantation of solid organs is limited by the presence of
natural antibodies to carbohydrate antigens on the cells of discordant species that
cause hyper acute rejection, antibody-mediated acute vascular rejection, and a
strong T cell-mediated immune response to xenogeneic MHC molecules.
And lastly, bone marrow transplants are susceptible to rejection, and recipients
require intense preparatory immuno-suppression. In addition, T lymphocytes in the
bone marrow graft may respond to alloantigens of the host and cause GVHD. Acute
GVHD is characterized by epithelial cell death in the skin, intestinal tract, and liver; it
may be fatal. Chronic GVHD is characterized by fibrosis and atrophy of one or more
of these same target organs as well as the lungs and may also be fatal. Bone
marrow transplant recipients also often develop severe immunodeficiency, rendering
them susceptible to infections.
In conclusion, future advances in tolerance induction will come from approaches that
exploit the normal mechanisms that establish and maintain self-tolerance.5 These
approaches may take the form of pharmacologic agents, biological agents, gene
therapy, or some combination. Recent studies suggesting that expression of the
Fas-ligand gene can make tissue sites immunologically privileged are an exciting
example of how this knowledge and technology can be put to practical use.
One of the foremost difficulties will be clinical trial design. To the extent that current
therapy provides excellent short-term outcomes, large studies with long observation
periods will be required to demonstrate that new strategies are superior.
Alternatively, trials might focus on high-risk patients (such as those undergoing re-
transplantation or experiencing rejection); however, the likelihood of seeing success
is concomitantly reduced. The problem of how to individualize treatment because no
treatment is uniformly successful should also be considered. With the present
medications, some patients are at low risk for rejection (and steroid therapy can
perhaps be withdrawn), whereas others have a higher risk.
The, there is also the issue of shortage of donors for patients willing to have
transplants. Because of this, there is a race for the successful development of
artificial organs. Thus, the sub-fields of regenerative medicine and
xenotransplantation will be up for some challenges and excitement.
5
Laurence A. Turka, What's New in Transplant Immunology: Problems and Prospects, Annals of Internal Medicine.
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