Lecture 31 (Tumor Immunology)

cancers are defined by the presence of what 5 key features?

-abnormal cell proliferation: loss of normal regulatory features that limit growth

-ability to spread to other portions of the body through metastases

-resist to cell death

-induce angiogenesis

-ability to avoid immune destruction

t/f: cancer appears to be more common in patients that have defective immune systems

true

BCG given intralesionally is a:

a) non-specific immune strategy
b) passive therapy
c) active therapy

a) non-specific immune strategy

infusion of MCA against a tumor antigen is a:

a) non-specific immune strategy
b) passive therapy
c) active therapy

b) passive therapy

vaccination against onogenic viruses is a:

a) non-specific immune strategy
b) passive therapy
c) active therapy

c) active therapy

patients that have long-term graft survival are more likely to develop _______________

malignancies

t/f: patients whose tumors have lymphoid infiltrates often have a poor prognosis

false - better prognosis

t/f: young and very old individuals have higher incidences of cancer

true

t/f: patients cannot be vaccinated to prevent specific cancers

false - they can be vaccinated

what are the 5 specific types of tumor specific antigens that can elicit an immune response?

1. Differentiation antigens (CDs expressed)
2. Mutated proteins (cKit)
3. Virally coded proteins (FOCMA)
4. Regionally Restricted Antigens (ProstateSpecificAg)
5. Excessive amounts of normal protein (Tyrosine)

therapeutic blockade of inhibitory receptors such as ________ and _______ leads to tumor remission

PD-1 and CTLA-4

recognition of tumor cells by the immune system requires the presence of ____________ antigens or __________ specific antigens to overcome self-tolerance

foreign antigens or tumor specific antigens

what is FOCMA?

Feline Oncornavirus-associated cell membrane antigen (Found on lymphoma cells)

cats that express antibodies against FOCMA are resistant to getting _____________

FeLV-LSA

-differentiation antigens
-proteins associated with specific stages of cell differentiation

a) CD antigens
b) c-kit
c) FOCMA
d) PSA
e) Tyrosinase

a) CD antigens

-mutated proteins
-altered forms of normal cellular proteins

a) CD antigens
b) c-kit
c) FOCMA
d) PSA
e) Tyrosinase

b) c-kit

-viral coded proteins
-products of genes of oncogenic viruses

a) CD antigens
b) c-kit
c) FOCMA
d) PSA
e) Tyrosinase

c) FOCMA

-cancer/testis antigens
-proteins of unknown function

a) CD antigens
b) c-kit
c) FOCMA
d) PSA
e) Tyrosinase

d) PSA

-excessive amounts of normal proteins
-over-production of normal cell products

a) CD antigens
b) c-kit
c) FOCMA
d) PSA
e) Tyrosinase

e) Tyrosinase

c-kit is a membrane associated signaling protein that is important for ______ _______ maturation and promotes growth and differentiation

stem cell

Tyrosinase:

Melanosome associated glycoprotein that is critical for _________ production

melanin

the most effective immune response to cancer is:

a) TH1
b) TH2
c) TH17
d) Treg

a) TH1

the most effective immune responses targeting tumors are _______ and ________ cell responses

CTL and NK cell responses

antigens are endogenously expressed in tumor cells and thus lead to ____________ expression

MHC I

which is more important in the immune response to tumors?

a) MHCI
b) MHCII

a) MHCI

which is more important in the immune response to transplants?

a) MHCI
b) MHCII

b) MHCII

antigen-specific CTLs are generated via interaction with APCs and _________

CD4s

what are the 4 big reasons the immune system fails in the context of tumor development?

1. tumor outgrows immune response
2. the tumor antigens are weakly antigenic
3. tumors develop resistance to immune recognition
4. tumor-bearing patients already have weakened immune systems

what are the 4 main ways tumors develop resistance?

1. reduced expression of antigens
2. reduced expression of MHC I
3. cytokine dysregulation (TGFβ, IL-10, etc.)
4. direct contact (upregulate inhibitory ligands)

tumors can upregulate or stimulate effect of inhibitors:

upregulate CTLA-4 transmits inhibitory signal to ________ costimulator

B-7

tumors can upregulate or stimulate effect of inhibitors:

upregulate PDL-1 expression: PD-1 cell surface receptor on T-cells and pro-B cells. activation promotes ___________

apoptosis

tumor derived cytokines can be immunosuppressive or inhibitory:

_________ induces growth arrest in benign epithelia and early tumors. pathways are dysregulated in advanced tumors and promote tumor growth

TGFβ

tumor resistance:

immune evasion can occur by what two things?

-reduced or absent expression of tumor antigens
-reduced or absent MHC I expression

T-cell subsets are altered in tumor bearing patients:

_______________ T-regulatory cells are increased in dogs with cancer

CD4+FoxP3+

there is a ____% increase in circulating Treg in tumor bearing dogs

50%

what lymphocyte ratio is prognostic in cancer patients?

CD8 : Treg

*the higher the CD8, the better

what are the three general strategies that can be used for tumor treatment?

-non-specific immune stimulants
-passive immunotherapy
-active immunotherapy

talk about non-specific stimulates used for tumor treatment

-bacterial products such as BCG
-Acemannan (complex carbohydrate)

*these function by activating macrophages, stimulating cytokine release, and promoting T-cell activity

talk about non-specific immune stimulates used for tumor treatment

*drug used in Europe*

cytokine therapy:

-IFNα, IFNβ, IFNγ, TNFα, and IL-2

-fll-2 vector available for feline fibrosarcoma

-Oncept IL-2

talk about passive immune stimulants used for tumor treatment

in vitro primed T-cell therapy:

-expression of T-cell subsets lower in tumor bearing patients

-combination of disease and therapy

-adoptive T-cell therapy improves outcome in canine lymphoma

monoclonal antibody therapy:

-target vascular stroma, tumor antigens, membrane death

-developed to treat many solid and hematogenous cancers

what two monoclonal antibodies were on the market to be used to target tumors?

-CD52-pan-lymphoid marker
-CD20-B-cell marker

talk about active immune stimulants used for tumor treatment

vaccination against oncogenic viruses:

-FeL V-Leukocell 2 vaccine has FOCMA antigen

-papilloma virus in humans

-Marek's disease in avian (HVT MLV vaccine)

DNA vaccination against tumor specific antigens

___________ blockade in melanoma, lung cancer
*monoclonal antibody called Ipilimumad (Yervoy)

a) CTLA-4
b) PD-1/PD-L 1

a) CTLA-4

___________ blockade in melanoma, lung
*monoclonal antibody called Nivolumad (Opdivo)

a) CTLA-4
b) PD-1/PD-L 1

b) PD-1/PD-L 1

what is the most common SQ tumor seen in cats?

feline fibrosarcoma

feline fibrosarcoma is strongly associated with _________________ vaccinations

FeLV/rabies

*2x increased risk with rabies
*5.5x increased with FeLV

what is the most common skin tumor of horses?

equine sarcoids

equine sarcoids is strongly associated with __________ __________ virus

bovine papilloma virus

what is the most common bone malignancy in dogs?

canine osteosarcoma

what immune stimulates are used to improve the outcome of canine osteosarcoma?

-L-MTP
-local infection
-cytokines

USDA approved tumor-directed immunotherapeutics

-Oncept IL-2
-Oncept melanoma
-canine lymphoma antibodies

-canary pox virus with DNA sequence for feline IL-2 insert
-designed to be injected intralesionally and result in local IL-2 expression
-feline fibrosarcoma
-no longer commercially available

a) Oncept IL-2
b) Oncept melanoma
c) canine lymphoma antibodies

a) Oncept IL-2

-pING plasmid with DNA sequence for human tyrosinase insert
-designed to be injected intramuscularly
-stimulates a cross response against canine tyrosinase
-canine oral melanoma

a) Oncept IL-2
b) Oncept melanoma
c) canine lymphoma antibodies

b) Oncept melanoma

-CD52-pan-lymphoid full canine antibody leads to ADCC
-complement mediated lympholysis
-CD20-B-cell specific full canine antibody
-no longer commercially available

a) Oncept IL-2
b) Oncept melanoma
c) canine lymphoma antibodies

c) canine lymphoma antibodies