Lecture 22

Question 1

What are the stages of immune response to tumor?

Answer 1

loss of genome stability
acquire mutations in proteins that may be seen as “foreign” by immune system
recognize by immune cells as “neoantigen” (antigens created by mutation)
immune surveillance: recognize/eliminate tumor before clinically detectable

Question 2

What happens when elimination of tumor is not complete?

Answer 2

proliferation causes additional changes or mutations, selection pressure influences which will survive

Question 3

What is cancer immunoediting?

Answer 3

tumors acquire mutation that favor cancer cell survival and escape from immune response

Question 4

How do tumors avoid immune recognition?

Answer 4

1. lack antigens recognized by T cells
2. lack co-stimulation as APC present neo-antigens lead to tolerance, treated as “self”
3. some lose expression of particular MHCI molecule, avoid recognition by CD8 while still resistant to NK
4. immunosuppressive microenvironments
5. produce materials like collagen, physical barrier to interaction

Question 5

What are examples of immunosuppressive microenvironments?

Answer 5

TGFb, myeloid cells inhibit T cell activation
some tumors express PD-L1, ligand PD-1 expressed by activated T cell
some produce IDO, which catabolizes tryptophan, an aa that produces immunosuppressive metabolite kynureine

Question 6

How do we prevent/treat cancer via immune system?

Answer 6

1. checkpoint blockade cancer immunotherapy
2. chimeric antigen receptor (CAR) T cells
3. monoclonal antibodies against tumor antigens
4. tumor vaccines

Question 7

What does a checkpoint blockage do?

Answer 7

some tumors express ligands for PD-1
T cells reacting to tumors w out PD-L1 do not encounter PD-1 inhibitory signal, may deliver cytotoxic action
tumors expressing PD-L1 can repress T cells, protected

Question 8

What are challenges with blockade of CTLA-4 and PD-1 in tumor immunotherapy?

Answer 8

1. autoimmunity
2. many patients don’t respond
3. possible tumor relapse due to upregulation of alt checkpoint, T cell exhaustion/dysfunction

Question 9

What happens in adoptive T cell therapy

Answer 9

ex vivo expansion of tumor specific T cells, infusion of those cells into patients
expand via Il-2, anti CD3 and allogenic APC
use of retroviral vectors to transfer tumor TCR genes into T cells before reinfusion

Question 10

How do chimeric antigen receptors (CARs) confer antitumor specificity to lymphocytes?

Answer 10

T cells taken. from patient –> lentivirus inserts CART-19 gene into T cells –> expand CAR expressing-T cells –> infuse back into patient, recognize/kill CD19+ tumor

Question 11

What is CART-19

Answer 11

chimeric antigen receptor composed of extracellular single-chain antibody that binds to CD19, which is fused to intracellular signaling domains from 4-1BB and CD3ζ chain

Question 12

How do monoclonal antibodies get used to eliminate tumors with NK cells?

Answer 12

antibody binds to tumor-specific antigen on cancer cell –> Fc part recognized by NK cells –> NK kills tumor cell

Question 13

How do monoclonal antibodies get used to eliminate tumors with toxins?

Answer 13

antibody linked to toxin (like chemotherapy molecule) –> endocytosed –> toxin released and kills from within

Question 14

How do monoclonal antibodies get used to eliminate tumors with radioactivity?

Answer 14

antibody linked to radioactive isotope –> binds to tumor cell, delivering direct radiation ** can hit nearby tumor cells too

Question 15

What is a cancer vaccine?

Answer 15

HPV (HPV-16) highly associated with cervical cancer, virus turns off P53, so viruslike particles (VLPs) generated into vaccine consisting of capsid protein L1 of HPV-16

Question 16

What are non-tumor factors that impact cancer immunotherapy response?

Answer 16

1. tumor intrinsic factors
2. host immune system
3. microbiome
4. diet and metabolisms
5. medications