Chapter 22: Tumor Immunology
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Chapter 22: Tumor Immunology

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Chapter 22: Tumor Immunology Chapter 22: Tumor Immunology Document Transcript

  • Chapter 22: Tumor Immunology 2 tumors benign or malignant / metastatic neoplasms carcinoma - leukemia - lymphoma - sarcoma - 3 Properties of Transformed Cells ______________________________ – starts with one cell cells divide indefinitely (immortal) cells don’t respond to growth controls - no contact inhibition in vitro biochemical / morphological changes chromosome abnormalities 4 Cells may be transformed by carcinogenic chemicals, radiation, viruses _________________________ viruses: Polyoma DNA viruses, Retroviruses (RNA) oncogenes (src, myc, ras) can _________________________ cells proto-oncogenes in normal cells (e.g. c-src) oncogenes code for cell growth or growth regulating proteins (kinases, G-proteins, etc.) 2 pathways to transformation 5 Three types of oncogenes genes that stimulate cell proliferation - code for __________________________________(src, ras) turning on or increasing expression → cancer genes that inhibit cell proliferation - _____________________________________________ genes turning off / inactivating → cancer e.g., Rb (retinoblastoma suppressor) gene p53 gene involved in many cancers __________________________________________ genes bcl-2 inhibits apoptosis in lymphocytes 6 Table of cancer genes 7 proto-oncogenes may become oncogenes random mutation caused by chemicals, radiation e.g., point mutations in c-ras genes rearranged by oncogenes – multiple copies viral integration into host chromosome alters transcription e.g., provirus in c-myc → increased synthesis of myc protein (transcription factor)
  • chromosome translocation – ex ___________________________________ chromosome 8 Cancer develops in stages colon cancer involves 4 genes - 3 tumor suppressor genes, 1 proliferation gene 9 Immune Cell Cancers ____________________________ – solid tumors (Hodgkin’s, Burkitt’s, NHL) leukemias – circulating cells acute lymphocytic (ALL) or myelogenous (AML) chronic (CLL or CML T / B cell cancers frequently involve Ig / TCR genes e.g., translocation of c-myc in Burkitt’s lymphoma 10 Tumor-Specific Transplantation Ags (TSTA) Found only on tumor cells (not normal cells) Some specific to a given tumor e.g. tumors induced by carcinogens - “private” tumor Ags like smokers’ cancer Other TSTA coded for by (DNA) viruses - same tumor Ags in all infected by the virus 11 Tumor-Associated Tumor Ags (TATA) on normal and tumor cells TATA may be expressed more on tumor cells EGF receptor: 100X more on tumor cells p97 (Fe transport protein) ___________________________________Ags – normal in fetal tissue AFP (α-fetoprotein) – seen in liver cancer CEA (carcinoembryonic Ag) – colon, lung, etc. oncogene products – cell proteins overexpressed neu gene expressed on breast cancer cells melanoma TATA ~ oncofetal Ags (MAGE, GAGE) 12 Four categories of Ags recognized by T cells Ags coded for by tumor genes Polyoma Virus T-Ag (TSTA) Ags from mutated normal genes (TSTA) differentiation Ags (TATA) Ags overexpressed in tumors (TATA) 13 Immune Response to Tumors - ____________________________ most important TC / CTL: direct activation & killing of tumor Ag-specific and MHC-restricted Problem -
  • ___________________ cells recognize / kill cells with no MHC can also kill by ADCC if Abs are present beige mice; Chediak-Higashi humans more tumors _________________________________________________ kill by ADCC or direct cytotoxicity TNF-α can kill tumor cells immune surveillance theory 14 Tumor Evasive Mechanisms Immune enhancement by ______________________________ blocking factors (Abs or immune complexes) Antigenic modulation – tumor loses / changes Ags decreased expression of __________________________on tumors no co-stimulating signal 15 Immunotherapy for Cancer enhance / provide co-stimulating signal melanoma cells transfected with _____________ gene enhance APC – transfect or culture w. cytokines tumor cells given GM-CSF gene → more APC culture dendritic cells with CK GM-CSF, IL-4, TNF-α → many more DC 16 __________________________ stimulate IR cytokines interferons IFN-γ stimulates NK, macs, T cells IFN-α → regression of some tumors all 3 IFNs increase MHC expression on tumor cells IL-2 activates _________________________________ TNF inhibits __________________________________ of tumors → necrosis 17 vaccines – e.g., virus Feline Leukemia Virus Marek’s disease (chickens) 18 activated cytotoxic cells ________ (lymphokine activated killer cells): culture pt NKC with IL-2 → inject back into pt side effects – vascular leakage syndrome _________ (tumor-infiltrating lymphocytes): culture tumor T cells with IL-2 Ag-specific killer cells
  • 19 MAbs anti-idiotype for B cell lymphoma MAbs vs. growth factor receptor (herceptin) ________________________________ (MAbs + toxin (diphtheria, etc.)