Cancer

Question 1

Cancer cells

Answer 1

Cells that suffer a mutation that alters characteristics of it
Mutations triggered by chemicals, radiation, viruses, or inherited defects in regulatory genes
Cells proliferating in an uncontrolled fashion will give rise to a growing clone of cells that eventually develops into a tumor or neoplasm
Several mechanisms are involved in tumor suppression: DNA repair, cellular senescence, etc

Question 2

Tumor Antigens: Neoantigens

Answer 2

Encoded by mutated genes
Not found on normal cells
A signal tumor can express several neoantigens

Question 3

Tumor antigens: Oncogenic viruses antigens

Answer 3

May elicit responses against the tumors

Epstein-Barr virus, papillomavirus

Question 4

Tumor antigens: overexpressed cellular proteins

Answer 4

Expression for longer times or at different locations
Abnormally high levels of expression
Not abnormal themselves but overexpressed

Question 5

Tumor creation

Answer 5

Founder cell (first cancer cells)- replicates at a faster pace- so more prone to further mutations
Then there is a tumor subpopulation (another mutation)
A third tumor subpopulation
Then there will be genetically heterogeneous tumor- will have several slightly genetically different clones

Question 6

Immune surveillance

Answer 6

1909 Paul erlich: hypothesis that host defense may prevent neoplastic cells from developing into tumors
1953 gross & foley: evidence of tumor stimulated IR
late 1950s Macfarlene burnet: tumor cell neoantigens induce an IR against cancer; immune surveillance theory

Question 7

Cancer immunoediting

Answer 7

2002 Dunn and schreiber
3 phases- not all need to be present
Elimination phase: tumor cells are killed by NK, CD4+ and CD8+ cells
Equilibrium phase: when the immune system is unable to destroy the tumor
Escape phase: appearance of clinically detectable tumors

Question 8

Immune surveillance: elimination (innate immune mechanisms)

Answer 8

Neutrophils

• produce TRAIL (TNF-related apoptosis-inducing ligand)
• stimulates apoptosis in tumor cells

NK cells
-express NKG2D which can bind MICA and MICB on many tumor cells

Question 9

NK cells

Answer 9

Failure to express MHC I

Expression of nonclassical molecules (MICA or MICB)

Question 10

Immune surveillance: elimination (macrophages)

Answer 10

Role in cancer immunity
Classically activated M1 macrophages can kill many tumor cells
Possibly recognized by DAMPs from dying tumor cells through macrophage TLRs
Activation of macrophages by IFN-y produced by tumor-specific T cells
Production of nitric oxide (NO)

M2 macrophages have been known to promote tumor growth through secretion of vascular endothelial growth factor (VEGF) and TGF-B

Question 11

Immune surveillance: elimination (adaptive immunity mechanisms)

Answer 11

CD8+ T cells: specific for tumor peptides presented on MHC class I can directly lyse tumor cells use perforins and granzymes 
CD4+ T cells: activated by APCs presenting tumor antigens leading to direct or indirect destruction of the tumor
-IFNy produced by CD4+ T cells activates macrophages 
NKT cells: recognize antigen presented by non-classical MHC class I molecules on tumor cells

Tumor-bearing hosts may produce antibodies against various tumor antigens
Antibodies may kill tumor cells by activating complement or by antibody-dependent cell-mediated cytotoxicity

If we successfully eliminate all cancer cells we would never know

Question 12

Immune surveillance: equilibrium

Answer 12

State in which tumor cells remain but do not progress
Tumor cells are not completely eliminated, but neither do they proliferate
-so immune system prevents growth and spread but cant get rid of it all the way
-most important aspect of cancer immunity is cell mediated response

Question 13

Cancer immunoediting

Answer 13

Tumor with enterogenous population-presenting different permutations which all present different Ag

Immune system can recognize some tumor antigen better than others

Will end up killing more than we recognize very efficiently

But what we cant recognize remains and replicates- selecting for more resistance tumor- so more resistant cell type predominates- escape of tumor from immune system
Natural selection of tumor cells

Question 14

Tumor escape

Answer 14

TGF-B (promoted tumor growth)
-induces tumor cell proliferation and angiogenesis
-suppresses elements of the host antitumor immune response
Indoleamine2,3-dioxygenase (IDO)
-suppresses T cell proliferation
Galactin-1
-stimulates angiogenesis
Programmed cell death ligand 1 (PDL1)
-slow down immune responses

Question 15

Tumor associated macrophages

Answer 15

M2 macrophages- can generate an anti-inflammatory environment within the tumor

• facilitates tumor spread
• stimulate angiogenesis
• interfere with ability to respond to tumors

Question 16

Immunological escape mechanisms

Answer 16

Highly similar to self
-no PAMPs (which is one of the first things to initiate responses)
Not all cells will express the same neoepitopes (because theyre diff slightly clones)
Switch off T cell responses
-IL-10 or TGFB
T cell checkpoint molecules
-CTLA-4, PD-L1
-anergy

Transformed cells frequently downregulate molecules that can facilitate T cell or NK-mediated attack (loss of MHC molecules or Tc epitopes, loss of ICAM-1) or upregulate/secrete molecules that can kill lymphocytes or that can anergize T cells that infiltrate the tumor

Question 17

Tumor immunotherapy

Answer 17

Passive immunization

• nonspecific immune stimulation
• -cytokine therapy
• -T cell therapy
• Monoclonal Ab against tumoral ag

Active immunization

• chemically modified tumor cells
• vaccination against oncogenic viruses
• -FeLV, Marek’s disease