The Immune System & Cancer

Question 1

Describe cancer cells.

Answer 1

-mutations triggered by chemicals, radiation, viruses, inherited defects in regulatory genes
-cells proliferating uncontrollably by growing clone of cells that develop into tumor/neoplasm
-mechanisms of tumor suppression: DNA repair, cellular senescence, apoptosis etc

Question 2

Describe the different types of tumor neoantigens.

Answer 2

1. Mutated proteins
   -altered versions of normal proteins
   -melanoma associated antigen recognized by T cells (MART1)
   -encoded by mutated genes & not found on normal cells
   -single tumor can express many neoantigens
2. Differentiation antigens
   -expression of antigens not normally found in adults (fetal only)
   -oncofetal antigens
   -carcinoembryonic antigen (CEA/CD66e) in GI tumors
3. Overexpressed cellular proteins
   -expression for longer times or at diff locations
   -abnormal high levels of expression (PSA in prostate cancer)
4. Oncogenic viruses antigens
   -response against tumor
   -FOCMA in FeLV cats/Mareks disease in chickens
5. Cancer/testis antigens
   -tumor antigens expressed in testes & various tumors

Question 3

Describe immune surveillance.

Answer 3

-1909 Paul Erlich
>host defense prevent neoplastic cells from developing into tumors
-1953 Gross & Foley
>tumor stimulated IR
-1950s MacFarlene Burnet
>tumor cell neoantigens induce IR against cancer
>immune surveillance theory

Question 4

Describe cancer immunoediting.

Answer 4

2002 Dunn & Schreiber
1. Elimination phase
-tumor cells killed by NK, CD4 & CD8 T cells
2. Equilibrium phase
-IS unable to destroy tumor
3. Escape phase
-detectable tumors

Question 5

Describe the immune surveillance elimination via the innate IS.

Answer 5

1. Neutrophils
   -make TAIL (TNF related apoptosis inducing ligand)
   -stim apoptosis in tumor cells
2. NK cells
   -failure to express MHCI
   -express non classical molecules (MICA/MICB)
   -express NKG2D = bind MICA/MICB on tumor cells
3. Macrophages
   -classically activated M1 macrophage kill tumor cells
   -recognize DAMPs from dying tumor cells thru macrophage TLRs
   -activate macrophage by IFNy made by tumor specific T cells
   -make NO
   *M2 macrophages = promote tumor growth thru secretion of vascular endothelial growth factor (VEGF) & TGF-B
   >can gen anti inflammatory environment within tumor

Question 6

Describe the immune surveillance elimination via the adaptive IS.

Answer 6

1. CD8 T cells
   -specific for tumor peptides presented on MHCI
   -directly lyse tumor cells using perforins & granzymes
2. CD4 T cells
   -activated by APCs presenting tumor antigens leading to direct/indirect destruction of tumor
3. NKT cells
   -recognize Ag presented by non classical MHC I on tumor cells
   *tumor bearing hosts make Ab against tumor antigens
   >Ab kill tumor cells by activating complement or by antibody-dependent cell-mediated cytotoxicity

Question 7

Describe equilibrium.

Answer 7

-tumor cells remain but dont progress
>not completely eliminated/dont proliferate

Question 8

Describe immunological escape mechanisms.

Answer 8

-similar to self
-no PAMPS
-not all cells express same neoantigens
-switch off T cell response
-tumor derived IL4, IL6, IL10, TGFB, PGE2, IDO
-T cell checkpoint molecules
>CTLA4, PDL1
>anergy

Question 9

Describe tumor escape: immunosuppression.

Answer 9

1. TGFB
   -induce tumor cell prolif & angiogenesis
   -suppress element of host anti tumor IR
2. Indoleamine 2,3 dioxygenase (IDO)
   -suppress T cell prolif
3. Galectin 1
   -stim angiogenesis
4. PDL1
   -slow down IR

Question 10

Describe transformed cells.

Answer 10

1. Downreg molecules that can facilitate T cell or NK mediated attack
   -ex. Loss of MHC, Tc epitopes, ICAM1
2. Upreg/secrete molecules that can kill lymphocytes
   -ex. FasL
3. Anergize T cells that infiltrate tumor
   -ex. PDL1, PDL2, IL10, IDO

Question 11

Describe tumor immunotherapy via nonspecific immune stimulation.

Answer 11

-cytokine therapy (interferons, TNFa, IL2, IL4)
-T-LAK cells
>gen by taking peripheral blood lymphocytes & activating them w IL2 & returning them IV
-microbial products
-checkpoint inhibitors

Question 12

Describe the principles of immune checkpoint therapy.

Answer 12

1. CTLA4
   -inhibitory receptor expressed on T cells
   -ligand = B7 expressed on cancer cells
   -blocking of CTLA4 by antibodies = cytotoxic T cells against tumor cells
2. PD1
   -blocks tumor cell apoptosis by binding to ligand PDL1
   >allows cytotoxicity & apoptosis

Question 13

Describe passive VS active immunization.

Answer 13

1. Passive
   -monoclonal Ab against tumoral Ag
2. Active
   -chemically modified tumor cells
   -vaccine against oncogenic viruses
   EX: FeLV, Mareks disease