Lecture 23: Tumor Immunity & Paraneoplastic Effects, Oncogenic Viruses, Diagnostic Tools

What is immunosurveillance?

the process by which the immune system attacks cells not recognized as self including transplanted tissues, microbes, or foreign cells (can be applied to tumor cells)

What are the proteins, glycoproteins, glycolipids, or carbohydrates expressed on tumor cells?

tumor antigens

True or false: tumor antigens are unique to only tumors.

false: can be tumor specific or tumor associated (expressed on tumor and normal cells)

True or false: type of immune response and effectiveness to a tumor is animal dependent and dependent on the tumor antigen expressed.

true

What is the innate immune response?

the first line of defense, largely involving NK cells and macrophages which do not require specific priming by DCs to kill cells

What is the adaptive immune response?

• cell mediated: DCs

• humoral: antibody mediated

What type of immune response is the most effective in anti-tumor activities?

cell mediated

What occurs in cell mediated tumor defense?

DCs capture antigen from dead or dying tumor cells, break them down, and present them on Class I and II MHC w/ appropriate costimulatory molecules to the effector cells (lymphocytes)

How do NK cells react to tumors?

1. recognize MHC molecules and stress induced ligands on tumor cells

2. bind to ligands and form immunologic synapse → release perforin and granzyme

3. apoptosis initiated

How do macrophages respond to tumor cells?

respond to interferon gamma produced by T lymphocytes and NK cells by killing tumor cells through the release of ROS, lysosomal enzymes, NO, and TNF alpha

How do B cells respond to tumors?

secreting immunoglobulins which activate the complement cascade and insert the MAC on tumor cells

What are the 4 main ways tumor cells inhibit/manipulate immune responses?

1. altered MHC expression

2. antigen masking

3. tolerance

4. immunosuppression

How do tumor cells alter MHC expression?

down regulate MCHI and MHCII expression to avoid detection; no MHCII no Th (CD4) response, but cells that fail to express MHCI are targeted by NK cells (delicate balance)

How do tumors use tolerance to evade the immune system?

express self antigens that are normally found on regular cells

How can tumors cause immunosuppression?

• TGF alpha production → inhibit growth and function of macs and lymphocytes

• expression of Fas ligand triggering apoptosis of T lymphocytes

Can tumors regress?

yes due to immune system clearing the tumor out NOT the neoplasm reverting back

What are two types of tumors that more commonly regress?

papillomas and canine cutaneous histiocytomas

What are paraneoplastic syndromes??

systemic clinical signs as a result of tumor (most often due to a malignant neoplasm)

How does humoral hypercalcemia of malignancy (HHM) occur?

neoplastic cells produce PTHrP which has a similar homology as PTH → stimulates calcium uptake in kidneys and bone breakdown to release calcium

What are the common neoplasias associated with PTHrP production and therefor HHM?

• anal sac gland adenocarcinoma (AGASACA)

• lymphoma

• various carcinomas

What is hypertrophic osteopathy?

a condition in dogs, cats, and horses resulting in typically symmetrical lameness due to periosteal new bone growth on long bones because of a space occupying mass in a chest cavity (does not have to be neoplastic)

What is occurring in this canine x-ray? You also find what appears to be a large mass on a thoracic image.

radiopaque thickening adjacent to cortical bone due to new bone deposition = hypertrophic osteopathy

What is the difference between cachexia and emaciation?

emaciation is preferential loss of fat stores first, before muscle due to malnutrition, whereas cachexia is the process of fat AND muscle loss occurring in chronic inflammatory states or cancer

What cytokines and hormones are increased in cachexia cases?

TNF alpha, IL-1, IL-6, and prostaglandins

What is the effect of the increased production of certain cytokines and hormones seen in cachexia cases?

cytokines act on hypothalamus in the brain → increased basal metabolic rate because animal is febrile (cancers can cause fever) → suppress appetite = anorexia and act directly on cells to increase demand of energy

Can neoplasia have an etiologic agent? If so, give an example.

yes, oncogenic viruses such as HPV or FeLV

What type of neoplasia does Marek’s disease cause and how?

gallid herpes virus-2 suppresses the ability of the host immune system to eliminate neoplastically transformed T cells → lymphoma

What are some clinical signs seen in Marek’s disease?

transient paralysis and iritic color changes due to neoplastic infiltrates

What type of neoplasia is caused by BLV (bovine leukosis virus) and how?

B-cell lymphoma induced by BLV inducing neoplastic transformation of lymphocytes

What organs/tissues are typically affected by BLV lymphoma?

heart, uterus, lymph node, abomasum, spinal cord

____ infection is associated with leukemias and thymic lymphoma in cats?

FeLV