Lec15 Tumor Immunity Flashcards Preview

Immunology > Lec15 Tumor Immunity > Flashcards

Flashcards in Lec15 Tumor Immunity Deck (45):
1

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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

2

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

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

3

What happens to T cells in mice following Tumor resection?

- get anti-tumor activity

4

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

Increased survival if have tumor infiltrating lymphocytes [TIL]

5

Do solid tumors express costimulatory molecules?

No

6

Do tumor cells or microbes express more antigen?

Microbes

7

Pathway of Effector T cell response against tumors

- 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

8

How are tumors distinguished from normal cells by immune system?

Expression of tumor associated antigens [TAA]

9

What are 5 main categories of TAA?

- 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

10

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

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

11

6 Major types of non-mutated TAA on human tumors

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

12

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

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

13

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

- non-mutated TAA present in human tumors
- in breast, colon, pancreatic tumors

14

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

- non-mutated TAA present in human tumors
- epidermal growth factor receptor
- in breast cancer

15

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

- non-mutated TAA present in human tumors
- in colon and breast cancer

16

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

- non-mutated TAA present in human tumors
- in melanocytes

17

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

- non-mutated TAA present in human tumors
- HPV E6 and E7: cervical cancer
- EBV: hodgkin's and nasopharyngeal carcinoma
- HBV and HCV: hepatocellular carcinoma

18

2 Main Mutated TAA on Human Tumors

- p21ras
- p53

19

What is p21ras? Mutated or non-mutated?

- cell cycle progression gene
- mutated TAA on human tumor
- in 10% of human tumors

20

What is p53? Mutated or non-mutated?

- tumor suppressor
- mutated TAA on human tumor
- ubiquitous mutation of metastatis/invasion

21

What are 5 mech why antigenic tumors not rejected?

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

22

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

- TGF-B
- IL-10
- secreted by T-reg and tumor cells

23

What is effect of tumor associated antigen loss variants?

- T cells don't see TAA, can't recognize tumor cells as different

24

What is effect of loss of MHC expression by tumors?

- 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