Immunity to Tumors

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Immunity to Tumors
Chapter 18
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• Cancer is a major health problem worldwide and
  one of the most important causes of morbidity and
  mortality in children and adults
• Cancers arise from the uncontrolled proliferation
  and spread of clones of transformed cells
• Benign and Malignant tumors, Metastases
• Immune surveillance (physiologic function of the
  immune System), Macfarlane Burnet 1950s

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General Features of Tumor Immunity

• Tumors stimulate specific, adaptive immune
  responses
• many tumors are surrounded by mononuclear cell
  infiltrates composed of T lymphocytes, natural
  killer (NK) cells, and macrophages, and that
  activated lymphocytes and macrophages are present
  in lymph nodes draining the sites of tumor growth

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• The first experimental demonstration that tumors
  can induce protective immune responses came from
  studies of transplanted tumors performed in the
  1950s (Methylcholanthrene, MCA)

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• Immune responses frequently fail to prevent the
  growth of tumors
• First, tumor cells are derived from host cells
  (weakly immunogenic)
• Second, the rapid growth and spread of tumors
• Third, many tumors have specialized mechanisms
  for evading host
• The immune system can be activated by external
  stimuli to effectively kill tumor cells and
  eradicate tumors (immunotherapy)

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Tumor antigens

• The earliest classification of tumor antigens was
  based on their patterns of expression
• tumor-specific antigens Antigens that are
  expressed on tumor cells but not on normal cells
• tumor-associated antigens Tumor antigens that
  are also expressed on normal cells
• The modern classification of tumor antigens
  relies on the molecular structure and source of
  the antigens
• To purify and characterize these antigens were
  based on producing monoclonal antibodies specific
  for tumor antigens
• A more recently developed approach for
  identification of tumor antigens specifically is
  called serologic analysis of recombinant cDNA
  expression (SEREX)
• Tumor antigens (peptides) that are recognized by
  T cells are likely to be the major inducers of
  tumor immunity and the most promising candidates
  for tumor vaccines

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1) Products of Mutated Genes

• Tumor antigens are produced by oncogenic mutants
  of normal cellular genes
• Often, these genes are produced by point
  mutations, deletions, chromosomal translocations,
  or viral gene insertions affecting cellular
  proto-oncogenes or tumor suppressor genes
• Peptides derived from them do not induce
  self-tolerance (circulating CD4and CD8T cells
  that can respond to them)
• Mutated oncogenes such as Ras and Bcr-Abl
  proteins and mutated tumor supressor genes such
  as p53

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P53 gene
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2) Abnormally Expressed Cellular Proteins

• Normal cellular proteins that are abnormally
  expressed in tumor cells and elicit immune
  responses
• One such antigen is tyrosinase, an enzyme
  involved in melanin biosynthesis that is
  expressed only in normal melanocytes and
  melanomas
• Tyrosinase-specific T or tyrosinase vaccines
• Cancer/testis antigens are proteins expressed in
  gametes and trophoblasts, and in many types of
  cancers, but not in normal somatic tissues (MAGE
  proteins expressed in other tumors in addition to
  melanomas, including carcinomas of the bladder,
  breast, skin, lung, and prostate, and some
  sarcomas)

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3) Antigens of Oncogenic Viruses

• The products of oncogenic viruses (DNA viruses)
  function as tumor antigens and elicit specific T
  cell responses that may serve to eradicate the
  tumors
• Epstein-Barr virus (EBV), B cell lymphomas and
  nasopharyngeal carcinoma,
• Human papillomavirus (HPV), cervical carcinoma
• Papovaviruses, including polyomavirus and simian
  virus 40 (SV40), and adenoviruses induce
  malignant tumors
• Because the viral peptides are foreign antigens,
  DNA virus-induced tumors are among the most
  immunogenic tumors known

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• RNA tumor viruses (retroviruses) are important
  causes of tumors in animals
• Human retrovirus that is known to cause tumors is
  human T cell lymphotropic virus 1 (HTLV-1), adult
  T cell leukemia/lymphoma (ATL), a malignant tumor
  of CD4 T cells
• Patients with ATL are often profoundly
  immunosuppressed, probably because the virus
  infects CD4 T cells

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4) Oncofetal Antigens

• Oncofetal antigens are proteins that are
  expressed at high levels in cancer cells and in
  normal developing fetal but not adult tissues
• These antigens are increased in tissues and in
  the circulation in various inflammatory
  conditions and are found in small quantities even
  in normal tissues
• Carcinoembryonic antigen (CEA) and a-fetoprotein
  (AFP)

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• Carcinoembryonic antigen (CEA)
• CEA (CD66) is a highly glycosylated integral
  membrane protein, of the immunoglobulin (lg)
  superfamily, an intercellular adhesion molecule
  that functions to promote the binding of tumor
  cells
• High CEA expression is normally restricted to
  cells in the gut, pancreas, and liver during the
  first two trimesters of gestation, and low
  expression is seen in normal adult colonic mucosa
  and the lactating breast
• CEA expression is increased in many carcinomas of
  the colon, pancreas, stomach, and breast
• The level of serum CEA is used to monitor the
  persistence or recurrence of the tumors after
  treatment

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• AFP is a circulating glycoprotein normally
  synthesized and secreted in fetal life by the
  yolk sac and liver
• Elevated in patients with hepatocellular
  carcinoma, germ cell tumors, and, occasionally,
  gastric and pancreatic cancers
• useful indicator of advanced liver or germ cell
  tumors or of recurrence

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5) Altered Glycolipid and Glycoprotein Antigens

• Most human and experimental tumors express higher
  than normal levels or abnormal forms of surface
  glycoproteins and glycolipids, which may be
  diagnostic markers and targets for therapy
• These altered molecules include gangliosides,
  blood group antigens, and mucins
• Melanomas are the gangliosides GM2, GD2, and GD3
• Clinical trials immunotherapy of anti-GM2,
  anti-GD3 and anti-GM2 antibodies in melanoma
• Mucins including CA-125 and CA-19-9, expressed on
  ovarian carcinomas, and MUC-1, expressed on
  breast carcinomas

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Ovarian ca
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6) Tissue-Specific Differentiation Antigens

• Tumors express molecules that are normally
  present on the cells of origin called
  differentiation antigens
• Several melanoma antigens that are targets of
  CTLs in patients are melanocyte differentiation
  antigens, such as tyrosinase
• Lymphomas may be diagnosed as B cell-derived
  tumors as CD10 (previously called common acute
  lymphoblastic leukemia antigen, or CALLA) and
  CD20
• Ig idiotype is a highly specific tumor antigen
  for B cell lymphomas and leukemias

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IMMUNE RESPONSES TO TUMORS
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Innate immune response to tumors

• NK Cells
• NK cells kill many types of tumor cells,
  especially cells that reduced class I MHC
  expression
• ADCC with FC?RIII
• The tumoricidal capacity of NKC is increased by
  cytokines, including interferons and interleukins
  (lL-2 and IL-12)
• lymphokine- activated killer (LAK) cells as
  adoptive immunotherapy, IL-2

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• 2. Macrophages
• In vitro, activated macrophages can kill many
  tumor cells more efficiently than they can kill
  normal cells
• Possible mechanisms include direct recognition of
  some surface antigens of tumor cells and
  activation of macrophages by lFN-? produced by
  tumor-specific T cells
• Activated macrophages also produce the cytokine
  tumor necrosis factor (TNF)

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Adaptive Immune Responses to Tumors

• Both T cell-mediated and humoral immune responses
• T Lymphocytes
• The principal mechanism of tumor immunity is
  killing of tumor cells by CD8 CTLs that
  associate with class I MHC molecules
• CD8T cell responses specific for tumor antigens
  may require cross presentation of the tumor
  antigens by professional APCs, such as dendritic
  cells in class II MHC
• APCs express class II MHC molecules that may
  present internalized tumor antigens and activate
  CD4 helper T cells
• Helper T cells specific for tumor antigens may
  secrete cytokines, such as TNF and IFN-?, that
  can increase tumor cell class I MHC expression
  and sensitivity to lysis by CTLs

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• 2. Antibodies
• Against various tumor antigens, as EBV-encoded
  antigens expressed on the surface of the lymphoma
  cells
• Antibodies may kill tumor cells by activating
  complement or ADCC

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Evasion of Immune Responses by Tumors

• Reduced immunogenicity, a process that has been
  called "tumor editing
• Tumor antigens may induce specific immunological
  tolerance
• Regulatory T cells may suppress T cell responses
  to tumors
• Tumors lose expression of antigens that elicit
  immune responses
• Tumors may fail to induce CTLs because most tumor
  cells do not express costimulators or class II
  MHC molecules
• The products of tumor cells may suppress
  anti-tumor immune responses, as TGF-ß or Some
  tumors express Fas ligand (FasL), glycocalyx
  molecules

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Tumors escape immune defenses
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Extrinsic Cellular Suppression ofAnti-Tumor
Immunity

• Tumor-associated macrophages (M2 phenotype) may
  promote tumor growth and invasiveness by altering
  the tissue microenvironment and by suppressing T
  cell responses
• Regulatory T cells may suppress T cell responses
  to tumors
• Myeloid-derived suppressor cells (MDSCs) are
  immature myeloid precursors that are recruited
  from the bone marrow and accumulate in lymphoid
  tissues, blood, or tumors of tumor-bearing
  animals and cancer patients and suppress
  anti-tumor innate and T cell responses

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Immunotherapy for Tumors

• Treating cancer has held great promise for
  oncologists and immunologists specific for tumor
  antigens and will not injure most normal cells
• Immunotherapy for tumors aims active immunity or
  to administer tumor-specific antibodies or T
  cells (passive immunity)

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Stimulation of Active Host Immune Responsesto
Tumors

• 1. Vaccination with Tumor Cells and Tumor
  Antigens
• Immunization with killed tumor cells or tumor
  antigens
• Identification of peptides recognized by
  tumor-specific CTLs
• And the cloning of genes with injection of
  plasmids containing cDNAs encoding tumor antigens
  (DNA vaccines)
• Tumor antigens, such as the MAGE, tyrosinase, and
  gp100 antigens on melanomas and mutated Ras and
  p53 proteins are potentially useful immunogens
• Virally induced tumors can be blocked by
  preventive vaccination with viral antigens or
  attenuated live viruses

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• 2. Augmentation of Host Immunity with
  Costimulators and Cytokines

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• 3. Blocking Inhibitory Pathways to Promote Tumor
  Immunity
• Inhibitory receptor for B7, called CTLA-4
• 4. Nonspecific Stimulation of the Immune System
• local administration of inflammatory substances
  (BCG) or,
• Systemic treatment with agents that function as
  polyclonal activators of lymphocytes (anti-CD3
  antibodies)

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Passive Immunotherapy for Tumors with T Cells and
Antibodies

• 1. Adoptive Cellular Therapy

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• 2. Graft-versus-Leukemia Effect
• In leukemia patients, administration of
  alloreactive T cells together with hematopoietic
  stem cell transplantscan contribute to
  eradication of the tumor
• 3. Therapy with Anti-tumor Antibodies
• Tumor-specific monoclonal antibodies (magic
  bullets) may be useful for specific immunotherapy
  for tumors
• Effector mechanisms including opsonization and
  phagocytosis and activation of the complement
  system
• Humanized mAB and immunotoxins

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Role of immune system in promoting of tumors

• Chronic inflammation (H. Pylori in gasteric ca.
  and chronic hepatitis B and C virus in
  hepatocellular ca.)
• Chronic activation of innate immune cells,
  notably macrophages, is characterized by
  angiogenesis and tissue remodeling, both of which
  favor tumor formation
• Innate immune cells can also contribute by
  generating free radicals that cause DNA damage
  and lead to mutations in tumor suppressor genes
  and oncogenes
• Mast cells, neutrophils, and macrophages, secrete
  soluble factors that promote celI-cycle
  progression and survival of tumor cells

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