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Lec15 Tumor Immunity Flashcards

1
Q

X

A

Lymphocytes that infiltrate tumors are preferentially CD3+ [either CD4 or CD8 subset]

analysis of TCR repertoire of T cells shows only some TCR not all are selectively recruited

growth of T cells in vitro yields populations able to make antigen specific responses to autologous tumor cells in vitro

t cells that react against autologous tumors can be isolated from some individuals

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2
Q

What are some things that if you take out you get spontaneous tumors [mice deficient in this get tumor]?

A 
RAG-1
RAG-2
perforin
IFN-gamma
IL-12
B2-microglobulin [light chain]
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3
Q

What happens to T cells in mice following Tumor resection?

A
  • get anti-tumor activity
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4
Q

How does presence of intratumoral T cell change survival in ovarian cancer?

A

Increased survival if have tumor infiltrating lymphocytes [TIL]

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5
Q

Do solid tumors express costimulatory molecules?

A

No

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6
Q

Do tumor cells or microbes express more antigen?

A

Microbes

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7
Q

Pathway of Effector T cell response against tumors

A
  • tumor cell expresses tumor associated antigen
  • tumor cell dies, falls apart, taken by pAPC [DC]
  • DC presents via MHC II to CD4
  • some antigen from phagolysosome leaks into cytoplasm and goes through endogenous path and presented by MHC I to CD8
  • CD8 differentiates to tumor-specific T cell and migrates to site of immunity to attack tumor
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8
Q

How are tumors distinguished from normal cells by immune system?

A

Expression of tumor associated antigens [TAA]

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9
Q

What are 5 main categories of TAA?

A
  • re-expression of germline sequences that are normally silent
  • re-expression of embryonic antigens
  • normal proteins expressed with point mutations
  • normal differentiation antigens overexpressed
  • oncogenic viral antigens
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10
Q

Which types of TAA are shared across multiple patients and which are unique? 5 total

A

shared

  • re-expression of germline sequences that are normally silent
  • re-expression of embryonic antigens
  • normal antigens but overexpressed
  • oncogenic viral antigens

unique
- normal proteins expressed with point mutations

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11
Q

6 Major types of non-mutated TAA on human tumors

A
  • cancer testis antigens
  • MUC1
  • HER2
  • CEA
  • MART-1/Melan A/tyrosinase
  • viral antigens [HPV E6/E7, EBV, HBV, HCV]
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12
Q

What are cancer testis antigens? Mutated or non-mutated? What types of tumors?

A
  • non-mutated TAA present in human tumors
  • in normal testis
  • expressed in solid tumor cells: melanoma, lung, bladder
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13
Q

What is MUC1? Mutated or non-mutated? What types of tumors?

A
  • non-mutated TAA present in human tumors

- in breast, colon, pancreatic tumors

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14
Q

What is HER2? Mutated or non-mutated? What types of tumors?

A
  • non-mutated TAA present in human tumors
  • epidermal growth factor receptor
  • in breast cancer
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15
Q

What is CEA? Mutated or non-mutated? What types of tumors?

A
  • non-mutated TAA present in human tumors

- in colon and breast cancer

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16
Q

What is MART-1/Melan A? Mutated or non-mutated? What types of tumors?

A
  • non-mutated TAA present in human tumors

- in melanocytes

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17
Q

What are viral antigens commonly in human tumors? Mutated or non-mutated? What types of tumors?

A
  • non-mutated TAA present in human tumors
  • HPV E6 and E7: cervical cancer
  • EBV: hodgkin’s and nasopharyngeal carcinoma
  • HBV and HCV: hepatocellular carcinoma
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18
Q

2 Main Mutated TAA on Human Tumors

A
  • p21ras

- p53

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19
Q

What is p21ras? Mutated or non-mutated?

A
  • cell cycle progression gene
  • mutated TAA on human tumor
  • in 10% of human tumors
20
Q

What is p53? Mutated or non-mutated?

A
  • tumor suppressor
  • mutated TAA on human tumor
  • ubiquitous mutation of metastatis/invasion
21
Q

What are 5 mech why antigenic tumors not rejected?

A
  • peripheral tolerance
  • secretion of inhibitory cytokines
  • tumor associated antigen loss variants
  • abnormal/loss of MHC expression by tumors
  • Tregs, myeloid-derived suppressors [MDSCs]
22
Q

What inhibitory cytokines keep T cells from attacking tumor cells? What are they secreted by?

A
  • TGF-B
  • IL-10
  • secreted by T-reg and tumor cells
23
Q

What is effect of tumor associated antigen loss variants?

A
  • T cells don’t see TAA, can’t recognize tumor cells as different
24
Q

What is effect of loss of MHC expression by tumors?

A
  • T cell can’t recognize tumor cells without MHC signal
25
Can anti-tumor immunity be lost? What causes decrease in anti-tumor immunity?
Yes, lose anti-tumor immunity with increasing tumor size
26
Do tumor cells grow more in presence or absence of CD4/CD25/Foxp3 Tregs?
- tumor cells induce Tregs | - tumor does not grow in absence of Tregs
27
What is generally first line treatment to treating malignancy?
Surgery
28
What is passive vs active immunotherapy
passive - does not induce T cells to have permament immunity/change - ex. infusion of antibodies or mature T cells to patient to attack tumor active - tumor vaccines directly stimulate patients own immune cells to respond to tumor
29
What things can immunotherapy involve
- antibodies - dendritic cells - t cells
30
3 Methods antibodies inhibit growth of cancer cells
- induce cytotoxicity together with cells - block receptors - act as vehicles to deliver immunotoxins
31
How do antibodies together wtih cells induce cytotoxicity?
Mediate antibody dependent cellular cytotoxicity [ADCC] - antibodies bind cell cell sruface antigen and recruit NK and eosinophils that bind Fc receptor of antibody - effector cell lyses target cell - usually NK except eosinophils for helminths
32
How do antibodies block receptors?
- prevent delivery of signals by growth factors
33
How are antibodies vehicles to deliver immunotoxins?
- act as agents to target toxic molec to cancer cells - immunotxoins can inhibit cellular function or induce DNA damage --> apoptosis - usually toxin or radionuclide
34
What is herceptin?
- also called trastuzumab - monoclonal antibody to HER-2 - HER-2 = epidermal growth factor receptor that is overexpressed on cell surface in breast cancer - herceptin blocks delivery of growth factor
35
RECIST [Response Evaluation Crieteria in Solid Tumors] Criteria of Clinical Trial Endpoints
complete response: disappearance of all tumor on radiographic image/visual inspection partial response: decrease more than 30% in dimensions of lesion disease progression: increase more than 20% in dimensions of any measurable lesion
36
What is combination therapy of herceptin?
- herceptin + chemotherapy together increase survival
37
What is Kadcycla?
- consists of herceptin antibody coupled to toxin DM1 - DM1 inhibits cell growth, induces apoptosis - approved for treatment Her2+ metastatic breast cancer - side effects: joint pain, muscle pain, thrombocytopenia, high liver enzymes, constipation, headache, fatigue, nausea
38
Are cancer vaccines prophylactic or therapeutic?
- therapeutic | - elicit CD4 or CD8 effector cells to contribute to tumor cell destruction
39
5 Types of Cancer vaccines
- Whole cell vaccines - tumor antigen vaccines - APC [DC] Vaccines - Non-specific therapy and cytokine therapy - combine reagents that failed individually
40
What are APC [DC] vaccines?
- inject modified APC that may better stimulate T cells - DC ingests cancer antigen [Ag] and presents it on MHC class I - DC migrates to lymph node and presents Ag to naive T cell's t cell receptor [TCR] - T cells differentiate, proliferate, become effector T cells and enter bloodstream - effector T cell TCRs bind Ag fragments presented on MHC-1 on cancer cells - T cell kills cancer cell
41
What is cytokine therapy
- increase maturation and growth APCs and T cells in vivo
42
How do whole cell tumor vaccines work?
- tumor cells have class I but do not have costimulator signal or promote secretion IL-2 - Do gene transfer to express B7/IL-2 in tumor cell so now tumor cell costimulates T cell - Get activation of tumor-specific T cells - IL-2 normally secreted by T cells is now secreted by tumor cells and will stimulate T cells around it
43
Adoptive T Cell Immunotherapy
- take tumor out of patient and isolate tumor infiltrating lymphocytes - grow TILs and test function - look for TIL that makes lots of IL-2 or IFN-gamma or whatever else you want using specific antibodies - Inject patient with autimmune lymphocytes
44
What is Ipilimumab?
- immunotherapy with anti-CTLA-4 - monoclonal antibody blocks CTLA-4 so prevents regulatory function - means B7 free to have positive costimulatory molec so get increased T cell ativation
45
What is provenge?
- for prostate cancer - take dendritic cells and feed it antigen from prostate cells - DC processes and expresses it - Infuse patient with activate DC/APC as a vaccine - causes activation of T cells in body that target prostate cancer cells - get 3 year overall survival

Immunology (17 decks)

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