Transcript HUIMM903cha17

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Immunity to tumors
• Tumor antigens
• Immune system’s reaction to tumor
antigens
• How tumors evade the immune
system
• Immunologic approaches to
treatment of cancer
Cancers arise from the uncontrolled
proliferation and spread of clones of
malignantly transformed cells.
Cancer is a major cause of disease and
death. About 1 of 5 deaths in
industrialised countries is from cancer.
The immune surveillance hypothesis
Frank Macfarlane Burnet 1956:
The immune system constantly checks
our cells, and detects and destroys
those that are malignantly
transformed.
Contra:
Most tumors are not more common in
immunodeficient individuals.
Exception: Virus-induced tumors.
Four reasons immune surveillance
may not work so well:
1) Tumors are «self», not «foreign».
They don’t have PAMPs, like
pathogens do.
2) Most tumor cells lack HLA class II
and costimulatory molecules.
3) Tumors that do not cause
inflammation may induce DCmediated tolerance.
4) Naive T cells circulate in blood,
lymph and secondary lymphoid
organs, and do not usually enter
peripheral tissues.
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Sign of immune reaction to tumor:
Lymphocytic inflammation.
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Demonstration
of tumor
immunity
Tumor antigens:
• Tumor-specific
Unique to individual tumors
Shared among tumors
• Tumor-associated
• Viral antigens
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Cloned CTL lines identify tumor
antigens from melanoma.
Some tumor antigens:
Mutated forms of cellular genes not
involved in tumorigenesis:
Various mutated proteins in
melanomas recognized by CTLs
Products of oncogenes and tumor
suppressor genes:
Oncogene products: Ras mutations
(∼10% of human carcinomas), p210
tyrosine kinase product of Bcr/Abl
chromosomal rearrangements (CML).
Tumor suppressor gene products:
Mutated p53 (present in ∼50% of
human tumors).
Unmutated but overexpressed
products of oncogenes:
HER2/Neu (tyrosine kinase; breast
and other carcinomas)
Products of genes that are silent in most
normal tissues:
Cancer/testis antigens expressed in
melanomas and many carcinomas;
normally expressed mainly in the testis
and placenta
Normal proteins overexpressed in tumor
cells:
Tyrosinase, gp100, MART in melanomas
(normally expressed in melanocytes)
Oncofetal antigens:
Silenced during development, derepressed with malignant transformation.
Diagnostic tools.
Carcinoembryonic antigen (CD66) on many
tumors, also expressed in liver and other
tissues during inflammation.
α-Fetoprotein (also elevated in some nonneoplastic diseases).
Glycolipids and glycoproteins:
• Gangliosides
• Mucins
Tissue-specific differentiation
antigens:
Prostate-specific antigen in prostate
carcinomas
CD20 on B cell lymphomas
Products of oncogenic viruses:
Papillomavirus E6 and E7 proteins
(cervical carcinomas)
HPV vaccination
EBNA-1 protein of Epstein-Barr Virus
(EBV-associated lymphomas,
nasopharyngeal carcinoma)
Immune responses to tumors
• Innate immunity
NK cells, macrophages
• Adaptive immunity
T lymphocytes, antibodies
NK cells
Kill many cells in vitro, especially
cells with low expression of MHC
class I.
ADCC
In vivo importance unclear.
LAK cells
Macrophages
M1 Mφ: Can kill tumor cells
M2 Mφ: Can promote tumor growth
The principal mechanism of adaptive
tumor immunity is killing of tumor
cells by CD8+ CTLs.
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Induction of CTL responses to tumors by
dendritic cell cross-presentation.
Antibodies
Little evidence for in vivo killing
of tumors by host antibodies.
Evasion of immune responses by
tumors.
Tumor editing – tumors become
less immunogenic over time.
Intrinsic mechanisms of evasion
• Loss of antigen expression
• Lack of costimulators or HLA
class II
• Inhibitory factors
Mechanisms
by which
tumors
escape
immune
defenses
Extrinsic factors
• Macrophages with M2 phenotype
• Regulatory T cells
• Myeloid-derived suppressor cells
Immunotherapy for tumors:
More specific and fewer side effects
than current therapies.
• Stimulation of active host immune
responses or
• Passive immunotherapy
Stimulation of active host immune
responses
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Vaccination with tumor antigens
Use of costimulators and cytokines
Blocking inhibitory pathways
Nonspecific stimulation
Tumor vaccines
Type of Vaccine Vaccine Preparation
Killed tumor vaccine Killed tumor cells + adjuvants
Tumor cell lysates + adjuvants
Purified tumor
antigens
Dendritic cell-based Dendritic cells pulsed with
vaccines
tumor antigens
Dendritic cells transfected with
genes encoding tumor
antigens
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Dendritic cell-based
tumor vaccines
Enhancement of tumor cell immunogenicity by
transfection of costimulator and cytokine genes
Counteracting T-cell inhibition.
N Eng J Med July 11 2013
Nivolumab: Anti PD1 receptor
Ipilimumab: Anti CTLA-4
(PD1 and CTLA-4 dampen T cell activity.)
Non-specific stimulation by systemic
cytokine therapy (a limited success).
IL-2 (Melanoma, renal & colon cancer)
IFN-α (Melanoma, carcinoid tumor)
TNF (Sarcoma, melanoma)
GM-CSF (to promote bone marrow
recovery)
Passive immunotherapy
• Adoptive cellular therapy
• Anti-tumor antibodies
Adoptive
cellular
therapy
LAK cells
Anti-tumor antibodies.
Mouse Ig is immunogenic for humans.
«Humanization» of mouse Ig.
-monab
-ximab
-zumab
-mumab
Mabs used in cancer treatment in Norway:
Alemtuzumab
CD52
Chronic lymphatic leukemia
Bevacizumab
VEGF
Several cancer forms
Cetuximab, Panitumumab
EGFR
EGFR+ colorectal cancer
Rituximab,
CD20
Non-Hodgkin lymphoma, chronic
lymphatic leukemia
Ofatumumab
CD20
Chronic lymphatic leukemia
Trastuzumab
Her2
Her2+ mamma cancer
Pertuzumab
Her2R
Her2+ mamma cancer
Ipilimumab
CTLA-4
Malignant melanoma
Catumaksomab
EpCAM + CD3
Malign ascites (ascites is
abnormal accumulation of fluid
in the abdominal cavity).
Promotion of tumor growth by
the immune system:
• Chronic inflammation
Hepatitis B
• Mutations caused by free radicals
• Growth factors
• M2 macrophages (VEGF, TGF-β)