CANCER IMMUNOLOGY is the study of interactions between the immune system and cancer cells (also called tumors or malignancies).immune systemcancertumorsmalignancies.

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1 CANCER IMMUNOLOGY is the study of interactions between the immune system and cancer cells (also called tumors or malignancies).immune systemcancertumorsmalignancies

2 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.immunotherapies 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.antigensvaccinesantibody

3 Aims (i)protection against development of spontaneous and chemically-induced tumors in animal systems (ii)identification of targets for immune recognition of human cancer

4 Cancer immunosurveillance lymphocytes act as sentinels in recognizing and eliminating continuously arising, nascent transformed cells lymphocytes Cancer immunosurveillance appears to be an important host protection process that inhibits carcinogenesis and maintains regular cellular homeostasis carcinogenesis homeostasis immunosurveillance primarily functions as a component of a more general process of cancer immunoediting

5 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

6 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 IFN- gamma.

7 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.

8 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.

9 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.

10 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 tumor- related immune response

11 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

12 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 VirusMouse Mammary Tumour Virus

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14 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.

15 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.

16 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

17 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)

18 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

19 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

20 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

21 Terapi Pengobatan simptomatis Kemoterapi – Non-Resistan – Resisten Radioterapi Interferon Terapi supportif