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Immunology > Lecture 21: Cancer Immunology > Flashcards

Lecture 21: Cancer Immunology Flashcards

1
Q

The cell cycle should ___ and enter ___ in most tissues of healthy, mature animals

A

Slow and enter Go (cell cycle arrest)

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2
Q

When does the cell cycle get reactivated in healthy individuals

A

Injury

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3
Q

What are some exceptions to the slowing down of the cell cycle

A

Skin and hair follicles, GI epithelium, bone marrow, male gametes

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4
Q

What regulates normal progression through cell cycle

A

Checkpoints

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5
Q

When does cancer occur in cell cycle

A

When mutations accrue in the DNA of cells that allow progression of the cell cycle without regulations at checkpoints and are passed on to daughter cells

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6
Q

What are the two classes of genes where mutation causes deregulation of cell cycle

A

Tumor suppressor genes and (proto)oncogenes

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7
Q

What are tumor suppressor genes

A

Genes that produce proteins that inhibit progression through cell cycle

Includes DNA repair enzymes and signaling proteins that block cell cycle

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8
Q

Are tumor suppressor gene mutations dominant or recessive

A

Recessive

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9
Q

What mutation is the most common cause of cancer

A

Tumor suppressor gene mutations

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10
Q

What are (proto)oncogenes

A

Genes that produce proteins that promote progression through the cell cycle (ex: respond to environmental factors like injuries)

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11
Q

What is the result of mutations in (proto) oncogenes

A

Cause constitutive activation of signaling proteins in growth pathways—> oncogenes

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12
Q

Are (proto)oncogene mutations dominant or recessive

A

Dominant

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13
Q

Are cancer viruses like FeLV cause tumor suppressor mutations or (proto) oncogenes

A

(Proto)oncogenes

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14
Q

Describe the timeline of mutations

A
  1. Mutation inactivates suppressor gene
  2. Cells proliferate
  3. Mutations inactive DNA repair mechanism
  4. proto-oncogenes mutate to oncogenes
  5. More mutations, more genetic instability, metastatic disease
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15
Q

Are mutated tumor suppressor genes and oncogenes driver or passenger mutations

A

Driver mutations

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16
Q

What are mutations that don’t deregulate the cell cycle

A

Passenger mutations

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17
Q

What mutations endow the cancer with other physiological changes that give them growth advantages

A

Passenger mutations

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18
Q

What mutations can be caused by continued exposure to carcinogens or radiation or arise spontaneously due to defective DNA repair enzymes

A

Passenger mutations

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19
Q

Mutations there avoid immune destruction, tumor promoting inflammation, and genome instability and mutation are examples of what kind of mutation

A

Passenger mutations

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20
Q

Does accumulation of mutations increase or decrease antigenicity of cancer cells

A

Increase

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21
Q

What are the two ways tumor antigens can be categorized as

A
  1. Tumor specific antigens (TSA’s) or mutation associated neoantigens (MANA’s)
  2. Tumor associated antigens (TAA’s)
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22
Q

What are TSA’s or MANA’s

A

Unique to tumor cells, result from mutations in the exons of any gene or incorporation of oncogenic viruses

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23
Q

What are TAA’s

A

Normal proteins that are inappropriately expressed by tumors, may be overexpression of a protein or expression of embryonic or other immune privileged protein, results form mutation in gene regulatory elements

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24
Q

What is immune surveillance

A

Capacity of immune system to recognize and destroy transformed cells before they grow into tumors and to kill tumors after they are formed

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25
Q

What observation supports immune surveillance hypothesis

A

The observation that immune compromised animals and humans have increased incidences of cancer

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26
Q

What does immune surveillance involve

A

Innate and adaptive immune responses

27
Q

What is the the tumor-specific CTL response to tumors

A

CTL’s are directed against tumor antigens presented by MHCI

28
Q

What is the antibodies response to tumors

A

Promote tumor cell destruction by enhancing innate immunity, serving as opsonins, activating complement and ADCC

29
Q

What is the immune response to tumors by NK cells

A

Capable of destroying tumor cells in non-MHC restricted fashion and are first line of defense against many tumors. They are effective against tumors with reduced levels of MHCI

30
Q

What is the immune response to tumors by macrophages

A

Strongly activated by IFN-gamma and kill with ROS and by secreting TNF. Macrophages also process and present tumor antigens to T cells

31
Q

What is the most important immune cell for tumor elimination/response

A

Cytotoxic T cells

32
Q

Describe the mechanism of elimination for CTL’s in tumor elimination

A
  1. Tumor antigens are picked up by dendritic cells at tumor site
  2. Activation of CTL’s in secondary lymphatics
  3. Tumor specific CTL’s migrate back to site and kill tumor cells

(May require cross-presentation with MHC I and MHCII)

33
Q

What is the mechanism of elimination for tumor elimination via NK cells

A

Recognize when MHCI expression goes down which occurs in immunosuppressive tumor environments

34
Q

What is the mechanism of elimination via Antibody dependent cell mediate cytotoxicity (ADCC)

A

NK cell recognizes antibodies bound to antigen and release toxic granules to kill antigen

35
Q

What is immunoediting

A

Describes how cancer cells respond to immune response

36
Q

What are the three steps of immunoediting

A
  1. Initiation/elimination
  2. Latent/equilibrium
  3. Clinical/escape
37
Q

What is the initiation/elimination phase of immunoediting

A

Initial cancer cells are immunogenicity

NK’s and CTL’s infiltrate and kill cancer cells

Immune system decreases tumor burden

38
Q

What is the latent/equilibrium phase in immunoediting

A

Killing by NK’s and CTL’s selects for cancer cells with fewer MHC I and MANA’s

Immune system keeps tumor in check

39
Q

What is the clinical/escape phase in immunoediting

A

Cancer cells promote immunosuppression

Immunosenescence may occur with age

Tumor growth outpaces immune system killing

40
Q

How does the immune system select for resistance in cancer

A

Immune cell killing is a selective pressure that results in survival and growth of tumor cells with reduced immunogenicity

41
Q

Do most cancer cells have more driver or passenger mutations

A

Passenger mutations

42
Q

Are most MANA’s driver or passenger mutations

A

Passenger

43
Q

Is immunity against the driver or passenger mutation

A

Most immunity is NOT against the driver

44
Q

What are examples of other cancer-cell associated mechanisms of immune escape

A
  1. Decreased MHC expression- reduces CTL expression
  2. Decreased expression of co-stimulatory molecules- causes CTL anergy and induces tolerance
  3. Expression of T-cell inhibitory receptors
  4. Normal immune attenuation
45
Q

What does PD-L1 do

A

Ligand for PD-1 which is a T cell inhibitory receptor, increases CTL apoptosis, and decreases Treg apoptosis

46
Q

What is CTLA-4

A

Homologous of CD28 that inhibits CTL function

47
Q

What is pro-tumor immunity

A

Tumors secreting cytokines that activate repressive cell typesh

48
Q

What cytokines are tumors secreting to activate repressive cell types

A

IL-4, IL-6, IL-10, TGF-B, MCF, and PGE2

49
Q

What are the two macrophages that are involved in pro tumor immunity

A

Myeloid derived suppressor cells and M2- polarized macrophages

50
Q

What are myeloid derived suppressor cells

A

Pre-myelocytes that express PD-L1 to inactive CTL’s and express more inhibitory cytokines

51
Q

What are M2-polarized macrophages

A

Promote blood vessel formation and tissue repair, do not phagocytose or secrete pro-inflammatory cytokines or ROS

52
Q

Regulatory T cells (Tregs) and pro-tumor immunity

A

Secrete IL-10 and TGF-B, inducing apoptosis of CD8 and CD-4 T cells, reducing available level of IL-2 by binding CD25

53
Q

What is piroxicam

A

Non-specific COX inhibitor that reduces tumor volume in Transitional cell carcinoma

Induces tumor cell apoptosis, possibly by reducing angiogenesis, PGE2 promotes angiogenesis

54
Q

What is mycobacterial cell wall fraction immunomodulator indicated for use in dogs

A

Mixed mammary tumors and mammary adenocarcinomas

55
Q

What is the indicated use for mycobacterial cell wall fraction immunomodulator in horses

A

Sarcoidosis, equine respiratory disease complex, metritis caused by streptococcus zooepidemicus

56
Q

What is the mechanism of mycobacterial cell wall fraction immunomodulator

A

Local injection that promotes inflammation, induces M1 macrophage activation and stimulates IL-1 release

57
Q

What are three potential treatments for lymphoma

A

Glucocorticoids- prednisone

Rabacofosadine and Asparginase

58
Q

What is the mechanism of action of prednisone/prednisolone in tx of lymphoma

A

Induces apoptosis of most lymphocyte classes, uses CHOP protocol- involves sequential administration of multiple drugs

59
Q

What is the mechanism of action for Rabacfosadine (Tanovea CA-1) in tx of lymphoma

A

Guanine nucleotide analog, does not have ribose base that DNA polymerase recognizes so terminates replication of DNA chains during S-phase

60
Q

What is the mechanism of action for asparaginase (Elspar) in tx of lymphoma

A

Enzyme that degrades circulating asparagine; deprives lymphoid cancer cells of a necessary amino acid and causes lethal metabolic stress

61
Q

What is Toceranib (Palladia)

A

Competitive antagonist of ATP binding to kinase domain of c-kit

62
Q

What is C-kit

A

Oncogene that is mutated in 20-50% of canine mast cell tumors

Signals continuously in absence of its ligand, causes unregulated cell proliferation of leukocytes, especially mast cells

63
Q

Is C-kit a passenger or driver mutation

A

Driver mutation

64
Q

What are some examples of anticancer vaccines

A
  1. FeLV
  2. Canine melanoma (oncept)
  3. Canine B cell lymphoma (Merial in clinical trials)
  4. Marek’s disease in chickens

Immunology (22 decks)

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