Tumor Immunity

Question 1

List 3 peices of evidence that immune system can recognize tumor “altered self” antigens

Answer 1

1. higher amount of T cell infiltration into tumor tissue correlates with a bettr prognosis
2. tumor transplants are rejected by an animal already exposed to that tumor (adaptive immune memory mediated by T cells)
3. Immunodeficient individuals have an incresaed incidence of some tumor types

Question 2

What is the cancer immunoediting concept? there are 3 stages explain them

Answer 2

1. Elimination
   
   1. Immune system is attacking the tumor
2. Equilibrium
   
   1. the tumor begins to modify
3. Escape
   
   1. the tumor evades the immune system and continues to grow

Question 3

What is the escape phase?

Answer 3

• immune responses frequently fail to prevent tumor growth. the immune system is designed to prevent “self” reactivity, so mechanisms are in place to prevent immune reactivity to cancerous cells.

Question 4

once we are in the escape phase and the tumor has evaded immune response are we doomed?

Answer 4

NO! there is hope. the immune system can be reactivated by external stimuli to kill tumor cells and elimate tumors

Question 5

What are the cells that are a part of the adaptive immune system

Answer 5

• Helper th1 CD4 T cells- provide stimulatory cytokines (IL-2, IFN-y)
• Cytotoxic CD8 T cells- killer cells secrete granzyme (serine proteases) and perforin
• B cells- soluble anti-tumor IgG and IgM adn complement-mediated killing

Question 6

How do T cells kill tumor cells if tumors are self?

Answer 6

• T cells are SELF-mutated, or SELF-overexpressed, non-self viral peptides

Question 7

What are the 4 signals that are requierd to produce activated effective anti-tumor CD8 CTLs?

Answer 7

1. Enaggement of TCR with MHC I presented tumor peptide on APC (DC, Macrophages, B cells)
2. Engagement of co-stimulatory ligands CD80/86 (APC) with activating receptors CD28 (T)
3. Effector/memeory cytokines (IFNy, IL-2, IL-5, IL-7, IFNab, IL-12)
4. upregulation of chemokine receptors required for T cell traficking

Question 8

once a T cell is activated does it require co-stimulation?

Answer 8

NO it is already active so its good to go

Question 9

What cells in the innate immune system are involved in tumor elimination

Answer 9

1. yDeltaT cells- recognize phosphoantigens expressed by tumor cells, are cytolytic and produce IFN-y and TNF-a. Express the gamma delta TCR not the classical alpha beta TCR
2. NK- produce IFN-y, tumor cytolytic-liberate tumor antigens to DCs induce DC activation and maturation
3. Dendritic Cells- secretion of Il-12 and type I IFNs and cross presentation of tumor antigen to CD8 T cells Immature DCs are tolerogenic
4. Macrophages: M1: proinflammatory mediators, M2 protumorigenic

Question 10

WHat cytokines are considered anti-tumor

Answer 10

• IFNy-activates macrophages, induces MHC class II, produced by activated NK and T cells
• IFNa and B-influene activation of innate and adpative immunity, viral
• IL-12L stimulates production of IFNy and TNF from T cells enhances cytotoxicity (self-amplify immune repsonse)
• TNF- acute phase inflammation
• NKG2D- stimulatory receptor, the ligand is overexpressed by infected, transformed, senescent and stressed cells
• TRAIL- death receptor ligand expressed on activated T cells
• Perforin-cytolic meiator produced by cytotoxic T cells

Question 11

How do cancer tumors have a barrier to the immune system

Answer 11

1. immune suppressive cell types
2. intrinsic spressive T cell mechanisms
3. immune inhibitory facotors in the tumor microenvironment

Question 12

WHat cells are involved in tumors ability to inhibit the immune system

Answer 12

• Immature/tolerogenic DCs
• Myeloid suppressor cells
• M2 macrophages
• T Regulatory cells
• Th2 CD4 T cells

Question 13

What is immunotherapy

Answer 13

mechanisms to ramp up T cell activation

antibodies that target tumor antigens resulting in tumor cell death

Question 14

What are the 8 ways to ramp up the T cells

Answer 14

1. Block the T cell inhibitory (checkpoint) receptors using blocking antibodies
2. Adoptive transfer of tumor-specific T cells
3. Gentically manipulate T cells for adoptive cell tranfer (chimeric antigen receptors of CAR T cells)
4. Allogenic T cells for anti-leukemia effect
5. Bispecific antibodies (direct T cell to target molecules)
6. Agonist antibodies to co-stimulatory T cell receptorsL CD40, CD137, ICOS, CD28, OX40
7. peptide, dendritic cell and DNA vaccines
8. immune stimulatory agents

Question 15

what are immune checkpoints and what do we use to block them

Answer 15

• a plethora of inhibitory pathways 9receptors/ligands) hardwired into the immune system (T lymphocytes, NK cells, B cells and others) to maintain self-tolerance and modulate the duration and magnitude of an immune response: cancers can co-opt these pathways to their advantage
• Monoclonal antibodies are used to interfere with immune suppression (block immune checkpoints)
• ex: CTLA-4 and PD-1

Question 16

What are two immune inhibitors

Answer 16

CTLA-4 and PD-1

Question 17

What cellular immunotherapy using TILs

Answer 17

• lymphocytes can be cultured from tumors by removing them in surgery.
• they are anti-tumor infiltrating lymphocytes
• TILs are expanded in culture and then give back to patients to provide large numbers of highly activated T cells that recognize cancer cells.
• this bypasses the suppressive mechanisms of the tumor

Question 18

What are Chimeric Antigen Rceptors?

Answer 18

CAR T cells

• A modified T cell that expresses their native antigen receptors and are able to become strongly activated when the antibody portion of the receptor binds to its antigen
• don’t need co-stimulation

Question 19

Allogenic T cells (Hematopoietic Stem Cell Transplantation) as Cancer Immunotherapy

Answer 19

Donor T cells that are transplanted to the host (patient) along with hematopoietic stem cell graft become activates to host alloantigens. While these activated donor T cells can attack host tissues and can cause graft-versus host disease (GVHD), they can also eliminate residual host cancer cells that express alloantigens

Question 20

What is BiTE?

Answer 20

Bispecific antibodies- T cell Engagers BiTE

BiTE gross the T cell and the Tumor and brings them together so the T cell can kill it. It is a way to bypass APCs

Question 21

what are agonist antibodies to co-stimulatory receptors

Answer 21

agonists to co-stimulatory receptors like CD40 and CD28. Help you get over needing co-stimulation. this isn’t that helpful though when you don’t have a lot of T-cells bc it wont’t make that big of an effect.

Question 22

WHat are dendritic cell vaccine

Answer 22

incubate DCs with tumor antigens, or gentically modify DCs to express tumor antigens. then you inject the DCs. this can help bypass the need for endogenous APCs in the body.

Question 23

What are DNA vaccines

Answer 23

DNA actiavtes the innate immune system. You encode the DNA so it encodes tumor antigen. you then inject this naked DNA that has tumor antigen into the patient and it is phagocytosed and the infor is presented by an APC and is a stimulant for T cell actiation

Question 24

What are whole cell tumor vaccines

Answer 24

remove some tumor cells ans then irradiate them to stop growth. then modify the genes and inject the irradiated tumor cells back in to stimulate the immune system!

Question 25

What are 2 antibodies that target tumor antigens

Answer 25

Trastuzumab- anti-HER2

Rituximab-anti-CD20

Question 26

what are 5 mechanisms by which antibodies can target tumor antigens

Answer 26

1. blocking cell survival signals
2. complement dependent cytotoxicity
3. antibody dependent cellular cytotoxicity
4. direct apoptosis
5. toxin delivery

Question 27

What can cancer antigens consist of?

Answer 27

1. mutated self proteins
2. mutates tumor suppressor genes ro oncogenes
3. overexpressed or abberantly expressed self proteins
4. oncogeneic viral proteins
5. post-translationally modified self proteins

Question 28

How do T cells need to see tumor antigens?

Answer 28

presented in the context of MHC and engagement with co-stimulatory molecules. the best source of this co-stimulation is provided by a professional APC such as a dendritic cell.

Question 29

Beside T cell stimulation what is needed to provide an effective CTL response

Answer 29

effector “Th1” cytokines and up-regulation of chemokine receptors is required to produce effective CTL response

Question 30

What are the signifacnt barriers to cancer immunity

Answer 30

1. cancer cells can modulate their antigen expression
2. produce suppressive factors
3. express or recruit suppressive (or regulatory) immune cells and myeloid suppressor cells and M2 macrohpages that produce ROS, iNOS, arginase, IL-10, PGE2 and express PD-L1

Question 31

tumors create barriers to cancer immunity. what needs to be donw to acheive effective anti-cancer immunity

Answer 31

these barriers must be turned off or bypassed

Question 32

How can we boost T cell activation

Answer 32

checkpoint blockade (antibodies that block signaling through PD-1 and CTLA-4, antibodies that activate T cell co-stimulatory receptors)

Question 33

How can we deliver tumor reactive T cells

Answer 33

adoptive cell transfer (ACT), allogenic T cells for leukemia, CAR T cells

Question 34

How can we increase presence of tumor antigens

Answer 34

vaccines and antibodies that directly target the tumor or killing

Question 35

How do we augment T cell trafficking to the tumor target

Answer 35

bi-specific antibodies (BiTES)

Question 36

How can we boost innate immunity to fight cancer

Answer 36

Toll-like receptor agonists

Question 37

How do we block immune suppressive factors/cells to fight cancer

Answer 37

IDO inhibitors