Transcript cancer immunology

CANCER IMMUNOLOGY
is the study of interactions between
the immune system and cancer cells
(also called tumors or malignancies).
Aim of research
• 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 as knowledge gained drives the
development of new vaccines and antibody
therapies.
Aims
(i) protection against development of
spontaneous and chemically-induced tumors
in animal systems
(ii) identification of targets for immune
recognition of human cancer
Cancer immunosurveillance
• lymphocytes act as sentinels in recognizing and
eliminating continuously arising, nascent
transformed cells
• Cancer immunosurveillance appears to be an
important host protection process that inhibits
carcinogenesis and maintains regular cellular
homeostasis
• immunosurveillance primarily functions as a
component of a more general process of cancer
immunoediting
Immunoediting
• is a process by which a person is protected
from cancer growth and the development of
tumour immunogenicity by their immune
system.
• It has three main phases:
– elimination, (4 phases)
– equilibrium and
– escape
Elimination
• Phase 1:
– the initiation of antitumor immune response
– Cells of the innate immune system recognise the presence
of a growing tumor which has undergone stromal
remodeling, causing local tissue damage.
– followed by the induction of inflammatory signals which is
essential for recruiting cells of the innate immune system
(eg. natural killer cells, natural killer T cells, macrophages
and dendritic cells) to the tumor site.
– the infiltrating lymphocytes such as the natural killer cells
and natural killer T cells are stimulated to produce IFNgamma.
• Phase 2
– newly synthesised IFN-gamma induces tumor death
(to a limited amount) as well as promoting the
production of chemokines CXCL10, CXCL9 and CXCL11.
– These chemokines play an important role in
promoting tumor death by blocking the formation of
new blood vessels.
– Tumor cell debris produced as a result of tumor death
is then ingested by dendritic cells, followed by the
migration of these dendritic cells to the draining
lymph nodes.
• Phase 3
– natural killer cells and macrophages transactivate one
another via the reciprocal production of IFN-gamma
and IL-12.
– This again promotes more tumor killing by these cells
via apoptosis and the production of reactive oxygen
and nitrogen intermediates. In the draining lymph
nodes,
– , tumor-specific dendritic cells trigger the
differentiation of Th1 cells which in turn facilitates the
development of CD8+ T cells.
• Phase 4
– the final phase of elimination, tumor-specific
CD4+ and CD8+ T cells home to the tumor site and
the cytolytic T lymphocytes then destroy the
antigen-bearing tumor cells which remain at the
site.
Equilibrium and Escape
• Tumor cell variants which have survived the elimination phase enter
the equilibrium phase.
• In this phase, lymphocytes and IFN-gamma exert a selection
pressure on tumor cells which are genetically unstable and rapidly
mutating.
• Tumor cell variants which have acquired resistance to elimination
then enter the escape phase
• In this phase, tumor cells continue to grow and expand in an
uncontrolled manner and may eventually lead to malignancies
• In the study of cancer immunoeditting, knockout mice have been
used for experimentation since human testing is not possible
• Tumor infiltration by lymphocytes is seen as a reflection of a tumorrelated immune response
Cancer Immunology and Chemotherapy
• A scientist investigate how inducing immunogenic cancer cell death
ought to become a priority of anticancer chemotherapy
• The immune system would be able to play a factor role in
eradicating chemotherapy-resistant cancer cells
• extensive research is still needed on how the immune response is
triggered against dying tumour cells
• He hypothesized that ‘apoptotic cell death is poorly immunogenic
whereas necrotic cell death is truly immunogenic’
• This is perhaps because cancer cells being eradicated via a necrotic
cell death pathway induce an immune response by triggering
dendritic cells to mature, due to inflammatory response stimulation
The role of viruses in cancer development
• Various strains of Human Papilloma Virus (HPV) have
recently been found to play an important role in the
development of cervical cancer
• The HPV oncogenes E6 and E7 that these viruses
possess have been shown to immortalise some human
cells and thus promote cancer development
• Although these strains of HPV have not been found in
all cervical cancers, they have been found to be the
cause in roughly 70% of cases
• A virus that has been shown to cause breast cancer in
mice is Mouse Mammary Tumour Virus
Multiple myeloma (MM)
• Multiple myeloma is a type of cancer.
• Myeloma is a cancer that starts in
plasma cells, a type of white blood
cell.
• It's the most common type of plasma
cell cancer.
Sifat MM
• “Multiple myeloma” bersifat maligna, yang terciri dengan
meningkatnya proliferasi sel plasma
• yang merupakan limposit sel B yang matang yang diproduksi
oleh sumsum tulang dan berfungsi untuk memproduksi
imunoglobulin yang diperlukan sebagai antibodi untuk
melawan infeksi penyakit.
• Dengan meningkatnya produksi sel B maka akan meningkat
pula sirkulasi imunoglobulin dalam peredaran darah.
• Peningkatan Ig tersebut akan berpotensi untuk berpengaruh
pada banyak organ dalam tubuh.
Gejala MM
• Penyakit MM ini sering menyerang orang pada usia lanjut, sering
ditemukan pada umur sekitar 60 tahun.
• Gejala yang diderita adalah rasa nyeri pada tulang, tulang patah dan
adanya infiltrasi sel tumor pada tulang sehingga menyebabkan tulang
mengalami degradasi sehingga tulang menjadi mudah patah.
• Kelelahan yang sangat (fatigue) karena anemia, penurunan sel darah
merah diganti oleh sel plasma yang diproduksi oleh sumsum tulang.
• Peka terhadap penyakit infeksi dan mengalami defisiensi imunoglobulin
yang normal.
• Pada pemerikasaan laboratorium dan analisis radiografi ditemukan
anemia karena penurunan sel darah merah.
• Kandungan kalsium dalam serum meningkat karena adanya degradasi
tulang , dimana “ Plasmocytomas” merangsang “Osteoclastic activating
factor (OAF)” yang menstimuli osteoclast merusak jaringan tulang
•
•
•
•
•
•
•
Gambar 7.5. Jaringan tulang mengalami degradasi dan menjadi rapuh.
•
•
Gambar 7.6. Gambaran elektroporesis dari serum darah normal (a) yang menunjukkan
angka gama globulin yang rendah (normal) dan tinggi (MM)( b)
Pemeriksaan laboratorium
• Penurunan jumlah sel darah merah (karena produksi sel darah
merah menurun)
• Kadar kalsium dalam serum meningkat (kalsium dalam tulang
terbongkar)
• Peningkatan kadar kimia serum darah (Blood urea nitrogen
/BUN, kadar kreatinin dsb)
• Peningkatan jumlah imunoglobulin (IgA, IgG, IgM, IgD dsb)
dengan metode elektroforesis dibandingkan normal
• Pada pemeriksaan ulas darah ditemukan formasi sel darah
merah bergandengan (formasi Rouleaux), ini terjadi karena
imunoglobulin sangat lengket sehingga sel darah merah
melengket satu dengan lainnya
• Pada pemeriksaan sumsum tulang terlihat banyak sel plasma
(sel darah muda) sekitar >10%. Ditemukan sel Mott, yang
merupakan sel plasma yang mengandung banyak vakuola
yang mengandung imunoglobulin
Terapi
• Pengobatan simptomatis
• Kemoterapi
– Non-Resistan
– Resisten
• Radioterapi
• Interferon
• Terapi supportif