Download Tumor-associated antigens

ATTA-UR-RAHMAN SCHOOL OF
APPLIED BIOSCIENCES (ASAB)
Clinical Immunology
Jasmina Makarevic
Fall Semester 2016
Tumor recognition is a complex, challenging problem for the immune system,
which must distinguish proper cellular growth and organization from neoplastic
transformation.
This process involves recognition of tumor antigens by effector cells and
induction of immunity. The development of tumors despite the presence of
antigens, the significance of immune recognition in the pathogenesis of
tumors, and the potential for therapeutic augmentation of immune responses
remain the subject of intense investigation.
Jasmina Makarevic
www.kgu.de/urologie
Tumor Immunology
Subcellular sources of tumor antigens.
Tumor-associated antigens (TAA) can derive from any protein
or glycoprotein synthesized by the tumor cell.
TAA proteins can reside in any subcellular compartment of
the tumor cell; ie, they may be
• membrane-bound
• cytoplasmic
• nuclear-localized,
• even secreted by the tumor cells
Those TAA of greatest clinical
interest are differentially expressed compared to the
corresponding normal tissue and allow for a preferential
recognition of tumor cells by specific T cells or immunoglobulins.
Jasmina Makarevic
www.kgu.de/urologie
Tumor- associated antigenes (TAA)
Many tumor cells produce antigens, which may be released in the bloodstream or remain on the cell
surface.
Antigens have been identified in most of the human cancers, including Burkitt lymphoma, neuroblastoma,
malignant melanoma, osteosarcoma, renal cell carcinoma, breast carcinoma, prostate cancer, lung
carcinomas, and colon cancer.
A key role of the immune system is detection of these antigens to permit subsequent targeting for
eradication. However, despite their foreign structure, the immune response to tumor antigens varies and is
often insufficient to prevent tumor growth.
Tumor-associated antigens (TAAs) are relatively restricted to tumor cells, whereas tumor-specific
antigens (TSAs) are unique to tumor cells. TSAs and TAAs typically are portions of intracellular
molecules expressed on the cell surface as part of the major histocompatibility complex.
Suggested mechanisms of origin for tumor antigens include
• Introduction of new genetic information from a virus (eg, human papillomavirus E6 and E7 proteins in cervical cancer)
• Alteration of oncogenes or tumor suppressor genes by carcinogens, which either generate a novel protein sequence
directly or induce accumulation of proteins that are normally not expressed or are expressed at very low levels (eg, ras,
p53)
• Abnormally high levels of proteins that normally are present at substantially lower levels (eg, prostate-specific antigens,
melanoma-associated antigens) or that are expressed only during embryonic development (carcinoembryonic antigens)
•Uncovering of antigens normally buried in the cell membrane because of defective membrane homeostasis in tumor cells
•Release of antigens normally sequestered within the cell or its organelles when tumor cells die
Jasmina Makarevic
www.kgu.de/urologie
Tumor Antigenes
The immune response to foreign antigens consists of humoral (eg, antibodies) and cellular
mechanisms.
Most humoral responses cannot prevent tumor growth.
However, effector cells, such as T cells, macrophages, and natural killer cells, have relatively
effective tumoricidal abilities.
Effector cell activity is induced by cells that present tumor-specific antigens (TSAs) or tumorassociated antigens (TAAs) on their surface (these cells are called antigen-presenting cells) and
is supported by cytokines (eg, interleukins, interferons—see Components of the Immune System :
Cytokines).
Despite the activity of effector cells, host immunoreactivity may fail to control tumor
occurrence and growth.
Jasmina Makarevic
www.kgu.de/urologie
Host response to Tumor
The T cell is the primary cell responsible for direct recognition and killing of tumor cells. T cells carry out immunologic
surveillance, then proliferate and destroy newly transformed tumor cells after recognizing TAAs. The T-cell response to
tumors is modulated by other cells of the immune system; some cells require the presence of humoral antibodies
directed against the tumor cells (antibody-dependent cellular cytotoxicity) to initiate the interactions that lead to the
death of tumor cells. In contrast, suppressor T cells inhibit the immune response against tumors.
Cytotoxic T lymphocytes (CTLs) recognize antigens on target cells and lyse these cells. These antigens may be cell
surface proteins or may be intracellular proteins (eg, TAAs) that are expressed on the surface in combination with
class I major histocompatibility complex (MHC) molecules. Tumor-specific CTLs have been found with
neuroblastomas; malignant melanomas; sarcomas; and carcinomas of the colon, breast, cervix, endometrium, ovary,
testis, nasopharynx, and kidney.
Natural killer (NK) cells are another population of effector cells with tumoricidal activity. In contrast to CTLs, NK cells
lack the receptor for antigen detection but can still recognize normal cells infected with viruses or tumor cells. Their
tumoricidal activity is termed natural because it is not induced by a specific antigen. The mechanism by which NK cells
discriminate between normal and abnormal cells is under study. Evidence suggests that class I MHC molecules on the
surface of normal cells inhibit NK cells and prevent lysis. Thus, the decreased level of class I molecule expression
characteristic of many tumor cells may allow activation of NK cells and subsequent tumor lysis.
Macrophages can kill specific tumor cells when activated by a combination of factors, including lymphokines (soluble
factors produced by T cells) and interferon. They are less effective than T-cell–mediated cytotoxic mechanisms. Under
certain circumstances, macrophages may present TAAs to T cells and stimulate tumor-specific immune response.
Jasmina Makarevic
www.kgu.de/urologie
Celullar Immunity
Dendritic cells are dedicated antigen-presenting cells present in barrier tissues (eg, skin, lymph nodes). They play a
central role in initiation of tumor-specific immune response. These cells take up tumor-associated proteins, process
them, and present TAAs to T cells to stimulate the CTL response against tumor. The presence of dendritic cells in
tumor tissues correlates with improved prognosis.
Lymphokines produced by immune cells stimulate growth or induce activities of other immune cells. Such lymphokines
include IL-2, also known as T-cell growth factor, and the interferons. IL-12 is produced by dendritic cells and specifically
induces CTLs, thereby enhancing antitumor immune responses.
Regulatory T cells are normally present in the body and help prevent autoimmune reactions. They are produced
during the active phase of immune responses to pathogens and limit the strong immune response that could damage
the host. Accumulation of these cells in cancers inhibits antitumor immune responses.
Myeloid-derived suppressor cells consist of immature myeloid cells and their precursors. These cells accumulate in
large numbers in cancers and potently suppress immune responses.
Jasmina Makarevic
www.kgu.de/urologie
Celullar Immunity
In contrast to T-cell cytotoxic immunity, humoral antibodies do not appear to confer significant
protection against tumor growth. Most antibodies cannot recognize TAAs. Regardless, humoral
antibodies that react with tumor cells in vitro have been detected in the sera of patients with various
tumors, including Burkitt lymphoma; malignant melanoma; osteosarcoma; neuroblastoma; and
carcinomas of the lung, breast, and GI tract.
Cytotoxic antibodies are directed against surface antigens of tumor cells. These antibodies can exert
anti-tumor effects through complement fixation or by serving as a flag for destruction of tumor cells by
T cells (antibody-dependent cell-mediated cytotoxicity). Another population of humoral antibodies,
called enhancing antibodies (blocking antibodies), may actually favor rather than inhibit tumor growth.
The mechanisms and relative importance of such immunologic enhancement are not well
understood.
Jasmina Makarevic
www.kgu.de/urologie
Humoral Immunity
Although many tumors are eliminated by the immune system (and thus are never detected), others
continue to grow despite the presence of TAAs. Several mechanisms have been proposed to explain
this deficient host response to the TAA, including the following:
• Specific immunologic tolerance to TAAs in a process that involves antigen-presenting cells and
suppressor T cells, possibly secondary to prenatal exposure to the antigen
• Suppression of immune response by chemical, physical, or viral agents (eg, helper T-cell destruction
by HIV)
• Suppression of the immune response by cytotoxic drugs or radiation
• Suppression of the immune response by the tumor itself through various complex and largely
uncharacterized mechanisms that cause various problems including decreased T, B, and antigenpresenting cell function, decreased IL-2 production, and increased circulating soluble IL-2 receptors
(which bind and hence inactivate IL-2)
Jasmina Makarevic
www.kgu.de/urologie
Failure Of Host Defenses
Tumor Immundiagnosis I
Carcinoembryonic antigen (CEA) is a protein-polysaccharide complex present in colon carcinomas and in normal
fetal intestine, pancreas, and liver. Blood levels are elevated in patients with colon carcinoma, but the specificity is relatively
low because positive results also occur in heavy cigarette smokers and in patients with cirrhosis, ulcerative colitis, and other
cancers (eg, breast, pancreas, bladder, ovary, cervix). Monitoring CEA levels may be useful for detecting cancer recurrence
after tumor excision if the patient initially had an elevated CEA and for refining estimates of prognosis by stage.
α-Fetoprotein, a normal product of fetal liver cells, is also present in the sera of patients with primary hepatoma,
nonseminomatous germ cell tumors, and, frequently, ovarian or testicular embryonal carcinoma. Levels are sometimes
useful for estimating prognosis or, less often, for diagnosis.
β Subunit of human chorionic gonadotropin (β-hCG), measured by immunoassay, is the major clinical marker in
women with gestational trophoblastic neoplasia (GTN)—a disease spectrum that includes hydatidiform mole, nonmetastatic
GTN, and metastatic GTN (see also Gestational Trophoblastic Disease)—and in about two thirds of men with testicular
embryonal carcinoma or choriocarcinoma. The β subunit is measured because it is specific for hCG. This marker is present
in low levels in healthy people. Levels are elevated during pregnancy.
Prostate-specific antigen (PSA), a glycoprotein located in ductal epithelial cells of the prostate gland, can be detected
in low concentrations in the sera of healthy men. Using an appropriate upper limit of normal, assays with monoclonal
antibodies detect elevated serum levels of PSA in about 90% of patients with advanced prostate cancer, even in the
absence of defined metastatic disease. It is more sensitive than prostatic acid phosphatase. However, because PSA is
elevated in other conditions (eg, benign prostatic hypertrophy, prostatitis, recent GU tract instrumentation), it is less specific.
PSA can be used to monitor recurrence after prostatic carcinoma has been diagnosed and treated.
Jasmina Makarevic
www.kgu.de/urologie
.
CA 125 is clinically useful for screening, diagnosing, and monitoring therapy for ovarian cancer, although any
peritoneal inflammatory process and some other cancers can increase levels.
β 2 -Microglobulin is often elevated in multiple myeloma and in some lymphomas. Its primary use is in prognosis.
CA 19-9 was originally developed to detect colorectal cancer but proved more sensitive for pancreatic cancer. It is
primarily used to judge the response to treatment in patients with advanced pancreatic cancers. CA 19-9 can also be
elevated in other GI cancers, particularly cancer of the bile ducts, and some benign bile duct and cholestatic disorders.
CA 15-3 and CA 27-29 are elevated in most patients with metastatic breast cancer. Levels may also be elevated in other
conditions. These markers are primarily used to monitor the response to therapy.
Chromogranin A is used as a marker for carcinoid and other neuroendocrine tumors. Sensitivity and specificity for
neuroendocrine tumors can exceed 75%, and diagnostic accuracy is higher with diffuse than with localized tumors.
Levels can be elevated in other cancers, such as lung and prostate, and some benign disorders (eg, primary
hypertension, chronic kidney disease, chronic atrophic gastritis).
Thyroglobulin is produced by the thyroid and may be elevated with various thyroid disorders. It is primarily used after
complete thyroidectomy to detect recurrent thyroid cancer and to monitor the response to treatment in metastatic thyroid
cancer.
TA-90 is a highly immunogenic subunit of a urinary tumor–associated antigen that is present in 70% of melanomas; softtissue sarcomas; and carcinomas of the breast, colon, and lung. Some studies have shown that TA-90 levels can
accurately predict survival and the presence of subclinical disease after surgery for melanoma.
Last full review/revision March 2013 by Dmitry Gabrilovich, MD, PhD
Jasmina Makarevic
www.kgu.de/urologie
Tumor Immundiagnosis II
Passive Immuntherapy
Lymphokine-activated killer (LAK) cells are produced from the patient’s endogenous T cells,
which are extracted and grown in a cell culture system by exposing them to the lymphokine IL-2.
The proliferated LAK cells are then returned to the patient’s bloodstream. Animal studies have
shown that LAK cells are more effective against cancer cells than are the original endogenous T
cells, presumably because of their greater number. Clinical trials of LAK cells in humans are
ongoing.
Tumor-infiltrating lymphocytes (TILs) may have greater tumoricidal activity than LAK cells.
These cells are grown in culture in a manner similar to LAK cells. However, the progenitor cells
consist of T cells that are isolated from resected tumor tissue. This process theoretically provides a
line of T cells that has greater tumor specificity than those obtained from the bloodstream. Recent
clinical studies have shown highly promising results.
Concomitant use of interferon enhances the expression of major histocompatibility complex (MHC)
antigens and tumor-associated antigens (TAAs) on tumor cells, thereby augmenting the killing of
tumor cells by the infused effector cells.
A new approach using T cells genetically modified to express receptors that recognize TAAs with
high specificity to tumor cells is under study and may provide significant clinical benefit. Results of
initial trials in patients with chronic lymphocytic leukemia are encouraging.
Jasmina Makarevic
www.kgu.de/urologie
In passive cellular immunotherapy, specific effector cells are directly infused and are not induced or
expanded within the patient.
Administration of exogenous antibodies constitutes passive humoral immunotherapy.
Antilymphocyte serum has been used in the treatment of chronic lymphocytic leukemia and in Tcell and B-cell lymphomas, resulting in temporary decreases in lymphocyte counts or lymph node
size.
Monoclonal antitumor antibodies may also be conjugated with toxins (eg, ricin, diphtheria) or with
radioisotopes so that the antibodies deliver these toxic agents specifically to the tumor cells.
Another technique involves bispecific antibodies, or linkage of one antibody that reacts with the
tumor cell to a second antibody that reacts with a cytotoxic effector cell. This technique brings the
effector cell in close opposition to the tumor cell, resulting in increased tumoricidal activity.
However, these techniques are in early stages of testing; thus, potential clinical benefits are
uncertain.
Jasmina Makarevic
www.kgu.de/urologie
Passive Humoral Immuntherapy
Inducing cellular immunity (involving cytotoxic T cells) in a host that failed to spontaneously develop an
effective response generally involves methods to enhance presentation of tumor antigens to host
effector cells. Cellular immunity can be induced to specific, very well-defined antigens. Several
techniques can be used to stimulate a host response; these techniques may involve giving peptides,
DNA, or tumor cells (from the host or another patient). Peptides and DNA are often given using antigenpresenting cells (dendritic cells). These dendritic cells can also be genetically modified to secrete
additional immune-response stimulants (eg, granulocyte-macrophage colony-stimulating factor [GMCSF]).
Peptide-based vaccines use peptides from defined TAAs. An increasing number of TAAs have been
identified as the target of T cells in cancer patients and are being tested in clinical trials. Recent data
indicate that responses are most potent if TAAs are delivered using dendritic cells. These cells are
obtained from the patient, loaded with the desired TAA, and then reintroduced intradermally; they
stimulate endogenous T cells to respond to the TAA. The peptides also can be delivered by coadministration with immunogenic adjuvants.
DNA vaccines use recombinant DNA that encodes a specific (defined) antigenic protein. The DNA is
incorporated into viruses that are injected directly into patients or, more often, introduced into dendritic
cells obtained from the patients, which are then injected back into them. The DNA expresses the target
antigen which triggers or enhances patients’ immune response.
Jasmina Makarevic
www.kgu.de/urologie
Active specific Immuntherapy I
Autochthonous tumor cells (cells taken from the host) have been reintroduced to the host after
use of ex vivo techniques (eg, irradiation, neuraminidase treatment, hapten conjugation,
hybridization with other cell lines) to reduce their malignant potential and increase their antigenic
activity. Sometimes the tumor cells are genetically modified to produce immunostimulatory
molecules (including cytokines such as GM-CSF or IL-2, costimulatory molecules such as B7-1,
and allogeneic class I MHC molecules); this modification helps attract effector molecules and
enhances systemic tumor targeting. Clinical trials with GM-CSF–modified tumor cells have
produced encouraging preliminary results.
Allogeneic tumor cells (cells taken from other patients) have been used in patients with acute
lymphocytic leukemia and acute myeloblastic leukemia. Remission is induced by intensive
chemotherapy and radiation therapy. Then, irradiated allogeneic tumor cells that have been
modified either genetically or chemically to increase their immunogenic potential are injected into
the patient. Sometimes patients are also given bacille Calmette-Guérin (BCG) vaccine or other
adjuvants (see Immunotherapy of Cancer : Nonspecific Immunotherapy) to enhance the immune
response against the tumor. Prolonged remissions or improved reinduction rates have been
reported in some series but not in most.
A novel approach to cancer treatment combining immunotherapy and conventional
chemotherapy has shown some success (vs historic controls) in nonrandomized phase I and
phase II clinical trials involving various cancers, types of vaccines, and chemotherapy.
Jasmina Makarevic
www.kgu.de/urologie
Active specific Immuntherapy II
Interferons (IFN-α, -β, -γ) are glycoproteins that have antitumor and antiviral activity. Depending on
dose, interferons may either enhance or decrease cellular and humoral immune functions. Interferons
also inhibit division and certain synthetic processes in a variety of cells. Clinical trials have indicated that
interferons have antitumor activity in various cancers, including hairy cell leukemia, chronic myelocytic
leukemia, AIDS-associated Kaposi’s sarcoma, non-Hodgkin lymphoma, multiple myeloma, and ovarian
carcinoma. However, interferons may have significant adverse effects, such as fever, malaise,
leukopenia, alopecia, and myalgias.
Certain bacterial adjuvants (BCG and derivatives, killed suspensions of Corynebacterium parvum)
have tumoricidal properties. They have been used with or without added tumor antigen to treat a variety
of cancers, usually along with intensive chemotherapy or radiation therapy. For example, direct injection
of BCG into cancerous tissues has resulted in regression of melanoma and prolongation of disease-free
intervals in superficial bladder carcinomas and may help prolong drug-induced remission in acute
myeloblastic leukemia, ovarian carcinoma, and non-Hodgkin lymphoma.
Jasmina Makarevic
www.kgu.de/urologie
Nonspecific Immuntherapy
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Thank You for Your Attention!
Jasmina Makarevic