Cancer and Immune System

• 2nd Leading cause of death

• Estimate ½ men & 1/3 women → cancer → 1/5 deaths (US)
• Homeostasis in cell number
• Altered self cells
• Unregulated mitosis
• Produces tumor (neoplasm)
• Benign – does not invade healthy tissue
• Malignant – grows and becomes invasive
• Exhibit metastasis
 Terminology & Types
• Neoplasm
• Benign & malignant
• Metastasis: Figure
• Classification according to embryonic origin of tissue
• Carcinoma : Epithelial cells (covering organs)
• Hematopoietic Cells: Leukemia (WBC), lymphoma (solid
tumor of immune system) & myeloma (plasma cells
cancer)
• Sarcoma (mesodermal)
• Leukemia
• Acute: fast, less mature cells; ALL & AML
• Chronic: slow, mature cells; CLL & CML
 Malignant transformation
• Induction by carcinogens: Chemicals, virus & radn.
• Features of in vitro cells
• Immortalization
• Anchorage independence
• Growth factor independence
• In vitro - In vivo correlation
• Mutagenicity & tumorgenicity
 ONCOGENES
• Rous sarcoma virus from chicken → induction of tumor in
other chicken
• Proto-oncogenes → mutation→ Cellular oncogenes (Normal
cellular genes)
• Cell cycle regulationincode products such as growth factors
and their receptors, cell cycle regulators, DNA-binding
proteins, transcription factors, protein kinases involved in
signal transduction, and others
• Viral oncogenes: Transforming genes carried by virus
Hallmarks of neoplastic transformation
• Sustained proliferation
• Subversion of negative regulators
• Resistance to cell death
• Replicative immortality
• Genetic instability
• Inflammation
 Revision
• Benign & malignant
• Metastasis
• Classification: Carcinoma, Sarcoma, Hematopoietic (Including
myeloma) & Neurological
• Factors
• Radiation, Mutagen & Viruses
• Mutation in cell cycle regulating Genes
• Growth factors and their receptors, cell cycle regulators, DNA-binding
proteins, transcription factors, protein kinases involved in signal
transduction, and others
Important cell cycle regulating genes
• Oncogenes: Sequences that encourage growth and
proliferation
• Tumor-suppressor genes: Sequences that discourage
or inhibit cell proliferation
• Apoptosis genes—sequences that control
programmed cell death
 Steps in malignant transformation
• 2 steps:
• Initiation: DNA alteration
• Malignant transformation: Rampant cell division to accumulate change
• Human colon cancer: A model to study cancers: Fig
• Cancer Progression: Multistep process
• Xeroderma Pigmentosa: Skin cancer upon UV exposure
• Defect in DNA repair gene
• Accumulation of altered DNA
• Autosomal recessive defect
• Cancer Stem Cells: True engine of tumor growth
Induction of cancer: Multi-step process
Colon cancer: A befitting eg
• Accessibility: colonoscopy
• Common disease in west: more studies
• P53 & Ras mutations on vivo
• Loss of heterozygousity (LOH) of TSG leading to
inactivation of TSG
• Activation of proto oncogenes
• More inactivation of TSG than activation of oncogenes
• Hypomethylation
• Exact sequence will differ (80% APC, 50% Ras,70% p53, 12% TGF-R
Tumor antigens
• 2 Types
• Tumor specific transplantation antigen
antigens (TSTAs):Viral or mutated protein
• Tumor Associated transplantation
antigens (TATAs)
• Humans: TSA & TAA
• Source of tumor antigens
• Only expressed by tumors (eg viral genes)
• Mutated genes
• Antigens expressed in abnormal stage of
development
• Over expression of normal antigen
 TSTA / TSA
• Specific to tumor type
• Unique to tumor types
• Not expressed in normal protein repertoire
• May be encoded by
• Viral genome
• Mutated alleles (ras, p53 or bcr-abl)
• Structurally novel
• Elicit Immune response: May be surface or internal protein
presented by MHC
• Chemically induced ag vs virally induced (eg HPV E6 & E7)
 TATAs or TAA
• Only associated not unique (normal cells may express)
• Expression not limited to malignant tissues
• No tolerance against them
• Attract immune response
• Eg. Oncofetal antigens upregulated by tumor cells
• Alpha fetoprotein (AFP): Normally In pregnant women but
also in liver, ovarian & testicular cancer
• Oncogene or Oncogene products: Growth factors &
Receptors
 Non Immune defenses against cancer
• Apoptotic machinery
• TSGs
• DNA repair apparatus
• Tissue differentiation
• Anoikis: PCD of anchorage-dependent cells when they
detach from the surrounding extracellular matrix
• Special status to stem cells
• IMMUNE SYSTEM: Self non self recognition
 Immune Response to Cancer
• Destroy viruses associated with cancer
• Elimination of pathogens & associated inflammation
• Identification and elimination of cancer cells (Immune
surveillance)
• Increased incidence in Immune suppressed patients
• Increased incidence in transplant patients
• Increased incidence in mice lacking T
cells/IFN/Recombinase activating Gene RAG gene ( T,B
& NK cells are compromised)
• Immuno editing: Influence of immune system on tumor
growth
Figures
 Immuno editing

Figure 15.19b The Biology of Cancer (© Garland Science 2007)

Tumor elimination by Innate Immune system
• NK Cells
• Chediak hegasi syndrome
• MHC Down regulation
• Perforin deficiency
• Secrete INF-γ
• ADCC
Tumor elimination by Acquired Immune
system
• Lack T cells: More susceptible
• More CTL: Tumor remission
• Tumor Infiltration lymphocytes: More tumor remission
• T cells
• NK cells
• NKT cells
• Kaplan Meir Plot: TIL & Disease remission
• B Cells: Anti tumor antibody
Ovarian Carcinoma

Figure 15.21d The Biology of Cancer (© Garland Science 2007)

 Role of Cytokines
• IFN-γ:
• NK cell ↑
• MHC I ↑
• Lacking it more tumor
• IL-12 ↑ Prevents chemically induced tumor
• Strong Th1 cells
• Strong CTLs
• Lacking: More Papilloma
• TNF- α
Table 15.3 The Biology of Cancer (© Garland Science 2007)
 Cancer Therapy

• Coley’s Toxin (1891): Injection with bacteria to remove

cancer
• Standard treatment
• Surgery, Chemotherapy, Radiotherapy & Hyperthermia
• Drug Therapy
• Block DNA synthesis
• Hormonal therapy
• Targeted therapy
• Immunotherapy
• Immunotherapy
 Cancer Immunotherapy
• Targeted mAb
• Direct
• Immunotoxin
• Chemical
• Radioactive particle
• Anti idiotypic antibodies: Figure
• Costume made: Personalized medicine (expensive)
• General: lineage specific: eg CD 20 (B cell marker) is
Rituximab
Cancer Immunotherapy
 Cytokines to enhance Immune response to
Tumours
• rDNA Tech: Source of cytokines
• Commonly used
• IFN (all 3)
• TNF (both)
• IL-2, 4, 6 & 12
• Combination
• Occasional results
• Toxicity
• Complex network
• High level requirement
Ex vivo expansion of T cells
• Enhancement of TILs activity
• How?
• Eg: Metastatic melanoma→ TILs → IL-2 → Expansion → lymphocyte
depletion to create niche → reinfusion → 50% regression in 10%
patient
• Therapeutic Vaccine: prophylaxis vs treatment:
• HPV & cervical cancer
• Fig