Download tumor immunology

The proliferation of normal cells is carefully regulated. However, such cells
when exposed to chemical carcinogens, irradiation and certain viruses
may undergo mutations leading to their transformation into cells that are
capable of uncontrolled growth, producing a tumor or neoplasm.
Benign: if it is not capable of indefinite growth and the host survives,
which are self-limited, and do not invade or metastasize.
Malignant if the tumor continues to grow indefinitely, metastasizes
(spread to other locations in the body via lymph or blood), eventually
killing the host.
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Most cancers form a tumor but some, like leukemia, do not.
Cancer causes about 13% of all human deaths.
Cancers can affect all animals.
Oncology.
The branch of medicine concerned with the study, diagnosis, treatment,
and prevention of cancer.
.
Carcinoma: Malignant tumors derived from epithelial cells. This group
represents the most common cancers, including the common forms of breast,
prostate, lung and colon cancer.
Sarcoma: Malignant tumors derived from connective tissue, or mesenchymal
cells.
Lymphoma and leukemia: Malignancies derived from hematopoietic cells.
Germ cell tumor: Tumors derived from totipotent cells. In adults most often
found in the testicle and ovary; in fetuses, babies, and young children most
often found on the body midline, particularly at the tip of the tailbone; in
horses most often found at the poll (base of the skull).
Blastic tumor or blastoma: A tumor (usually malignant) which resembles an
immature or embryonic tissue. Many of these tumors are most common in
children.
CANCER
Up regulation of
Oncogenes
Proto-oncogene:
RAS,WNT,MYC,
ERK,TRK
Down regulation of
Tumorsuppresser gene
P53,APC,CD95,ST5,
ST17,ST14
Virus
induced tumors
DNA Viruses
Papova virus
Hepatits virus
Adenovirus
RNA Viruses
Retrovirus
HTLV-I,
HTLV-II
Chemical
Induced Tumor
Pesticides
Synthetic drugs
Herbicides
Experimental Evidence for Tumor Antigens and
Immunr Response
1. Inject Tumor
2. Excise tumor
3. Re-challenge with
same tumor
4. No tumor
growth
1. Inject Tumor
2. Excise tumor
3. Re-challenge with
different tumor
4. Tumor
grows
Dendritic cell and tumor immunity
Indoleamine2,3-dioxygenase
(IDO)
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Biochemical properties of IDO
• IDO is a monomeric protein containing heme and encoded by a gene
over 15 kbp of DNA located on the short arm of chromosome 8 in
humans and mice (Mellor AL et al., 2004).
• The indoleamine 2,3-dioxygenase-like protein (INDOL1 or IDO2)
gene was recently identified and found to locate adjacent to the IDO
gene in mice and human (Ball HJ et al., 2007).
• The signaling of IDO activation occurs mainly through (JAK-STAT)
and (NF-κB) pathway (Mellor AL et al., 2004).
• IDO might bridge between DCs and Tregs (Puccetti P et al., 2007).
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Kynurenine
Pathway
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Fate of Tryptophan
General protein
synthesis
Serotonin
biosynthesis
Catabolism
through the
kynurenine
pathway
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IDO Molecular genetics and
enzyme activity
IDO transcription act through
JAK–STAT signaling pathways
on INF stimulatory response
elements (ISREs) and γactivating sequences (GAS) in
the IDO promoter.
Transcriptional repressor of
IDO are not defined, cis and
perhaps
trans-regulatory
factors are inferred.
No specific post-translational
modifications of IDO have yet
been identified . Functional
activity might also be regulated
at the level of holoenzyme
assembly (that is, incorporation
of the haeme prosthetic group).
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Essential amino acid deficiency antagonizes
signalling through the mTOR (mammalian
target of rapamycin) kinase pathway. mTOR
signalling is required for normal initiation of
ribosomal translation. This pathway is
important for growth-factor signalling, and T
cells are particularly sensitive to inhibitors
of mTOR, such as the immunosuppressant
drug rapamycin. A second amino-acid
responsive pathway is initiated by the GCN2
kinase, which contains a binding domain
that is specific for the uncharged form of
transfer RNA (tRNA). Precisely how
activating this stress-response pathway or
inhibiting the mTOR pathway might affect
the programme of T-cell activation is
currently unknown.
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Interactions between the tumour and cells of the immune system that
foster an immunosuppressive microenvironment.
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Andrew L. Mellor and David H. Munn.
Before
• IDO was thought to participate in innate host defence against
pathogens.
1998
After
1998
2004
• They proposed that IDO also has a role in immune regulation, as
inhibiting IDO during pregnancy in mice allowed maternal T cells
to attack allogeneic fetal tissues.
• Many studies had identified IDO as a component of the
inflammatory response associated with infection, cancer and
autoimmune and allergic diseases.
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Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory
target of the cancer suppression gene Bin1, potentiates cancer
chemotherapy.
(Muller, A. J et.al.2005) Nature Med. 11, 312–319
Three key questions were unresolved
The role of IDO in
The molecular
immune regulation and The origin and biological
mechanisms that
the therapeutic potential
significance of ‘IDOexplained IDO-mediated
of manipulating IDO
competent DCs?
regulation of immunity?
activity?
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Substantial progress on all three issues has been made in
the last 7 years.
IDO has been shown to control local innate immunity (inflammation) and to
regulate antigen-specific adaptive immune responses in settings as diverse as
mucosal tolerance, asthma, acquired tolerance to allograft, chronic infection and
tumour-induced immunosuppression.
In the case of cancer, IDO expression reported in patients with malignancy.
Treating tumour-bearing mice with IDO inhibitors enhances tumour-specific
immunity and synergizes with cytotoxic chemotherapy to improve treatment of
established tumours (Munn et. al 2011), and IDO inhibitors have recently
entered Phase II oncology trials.
• IDO expression is also a common feature of autoimmune, allergic and graftversus-host diseases, and in these settings IDO inhibition markedly
exacerbates disease severity.
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Infectious disease
IDO
inhibits
pathogen
replication appears to apply
in some settings.
In other settings, pathogeninduced IDO may attenuate
host
T
cell
immune
responses and facilitate the
persistence
of
certain
infections, such as HIV and
tuberculosis (Favre, D. et
al.2010),(Desvignes, L.et al.
2009) Thus, depending on
the pathogen, IDO may help
or hinder antimicrobial
immune responses, and this
is an active area of research.
Transplantation
David Wilkes and colleagues
first showed that IDO gene
transfer protected lung
allografts, pancreatic islet,
skin and corneal allografts.
Of note, overexpression of
IDO in transplanted lungs
profoundly
impairs
the
cytotoxic functions of host T
cells that infiltrate the
allografts (Liu, H. et al.2009).
IDO helps to establish
acquired
immunological
unresponsiveness at sites of
inflammation.
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