Immunobiology of Tumors and Immunotherapy

What is a tumor?

Cells proliferating in an uncontrolled fashion

What causes tumors?

Mutations in cells triggered by chemicals, radiation, or viruses

What are the types of tumors?

Benign and malignant

What are benign tumors?

A tumor clustered at a single site

There is no spread by blood or lymph

What is a malignant tumor?

A tumor that spreads from one site to other parts of the body through blood or lymph by metastasis

Which tumor type is harder to manage and treat?

Malignant tumors

What is melanoma?

Skin cancer from cells producing melanin pigment

What is a carcinoma?

Cancer of epithelial cells

What is a sarcoma?

Cancer of bones and soft tissues

What is a myeloma?

Cancer of plasma cells

What is leukemia?

Cancer of blood cells that originate in bone marrow

What is lymphoma?

Cancer of the immune system organs

What are tumor antigens?

Abnormal proteins expressed by tumor cells on their surface

What are tumor-specific antigens?

Antigens only found in tumor cells, either unique or significantly altered

What's an example of a tumor-specific antigen?

Melanoma-associated antigen (MAGE) in melanoma

What are tumor-associated antigens?

Normal proteins that overexpressed in tumor cells

What's an example of a tumor-associated antigen?

Prostate-specific antigen (PSA) in prostate cancer

What are the five major types of tumor antigens?

Differentiation antigens

Mutated proteins

Viral coded proteins

Cancer/testis antigens

Excessive amounts of normal proteins

What are differentiation antigens?

A tumor antigen that's a protein associated with a specific stage of cell differentiation

What's an example of a differentiation antigen?

Oncofetal antigens like carcinoembryonic antigen (CEA) in colon or rectal cancer

What are mutated proteins?

Tumor antigen that's an altered forms of normal cellular proteins

What is an example of a mutated protein?

MAGE in melanoma

What are viral coded proteins?

Tumor antigen that's the product of genes of oncogenic viruses

What's an example of a viral coded protein?

v-src ongogene in Rous Sarcoma in chickens

What are cancer/testis antigens?

Tumor antigens of unknown function

What do diseases cause that increases the risk of developing cancer?

Chronic inflammation

How does chronic inflammation increase the risk for cancer?

Increases DNA damage

Promotes cell proliferation and decreases apoptosis

Cytokines and chemokines released through the NF-kB and STAT3 pathways support cancer growth

What are homogenous malignancies?

Tumor cells with identical new antigens

What are heterogenous malignancies?

Tumor cells with dissimilar new antigens

What can cancer suppress in the host?

Immune system

What are ways that cancer cells induce immunosuppression?

By releasing immunosuppressive molecules and cells

Blocking antibodies

Blocking T cell immigration

Exhausting T cells and depleting proteins

What are the major cell types involved in tumor destruction?

T cells

Macrophages

NK cells

How do T cells recognize tumor cells?

Through tumor antigens expressed by MHC I

How do NK cells recognize tumor cells?

Through the recognition of stress related proteins expressed by the tumor cell

Through tumor cells downregulating MHC I

What cytokines are involved in tumor destruction?

IFN-gamma, IL-2, IL-12, TNF-alpha

What cells release IFN-gamma during tumor destruction?

T cell and NK cell

What cells release TNF-alpha during tumor cell destruction?

Macrophage

What macrophages are involved in tumor destruction?

M1 macrophages

How are tumors managed?

Surgical removal

Chemotherapy or radiation therapy

Immunotherapy

Immuno-modulation

Vaccines

What are the types of cancer immunotherapy?

Active and passive

What is active immunotherapy?

When the patient's own immune system is stimulated

What is passive immunotherapy?

When immune cells or products are administered to the patient

What are some examples of passive immunotherapy?

Monoclonal antibodies

Adoptive cell transfer

Immune checkpoint therapy

What are methods of stimulating the host immune system?

Immune stimulants to activate NK cells, macrophages, and CTLs

Repress regulatory cells

Use immunotoxins so host can recognize the toxin

What are examples of active immunotherapy methods?

Vaccines like Bacille Calmette-Guerin for mycobacterium bovis

Tissue damage and inflammation

What is Bacille Calmette-Guerin?

A vaccine that activates macrophages to release TNF-alpha, IL-12, and NO

Treats equine sarcoids

An example of active immunotherapy

How is tissue damage/inflammation active immunotherapy?

Tissue exudate/DAMPs stimulate the immune system

What's a disease where the active immunotherapy method of causing tissue damage can be a treatment?

In horses with Bovine papilloma virus warts

What is adoptive cell transfer?

Passive immunotherapy method where T cells are isolated and expanded before being returned to the patient

What is monoclonal antibody therapy?

Giving antibodies specific for a receptor to cause clearance of tumor cells

What do immune checkpoint inhibitors target?

CTLA-4 and PD-1/PD-L1 molecules

CTLA-4 and PD-1/PD-L1 molecules are targets for what?

Immune checkpoint inhibitors/ monoclonal antibodies

What is CTLA-4?

Inhibitory receptor on T cells

What is PD-1?

Receptor that blocks tumor cell apoptosis by binding to its ligant PD-L1

What happens when monoclonal antibodies are given?

They block CTLA-4 to allow CTLs to eliminate T cells

They block PD-L1 to allow T cell mediated cytotoxicity and apoptosis of tumor cells

What is the primary objective of cancer vaccines?

Activate tumor-specific T cells

What are the approaches to cancer vaccines?

Target tumor cells

Prime dendritic cells with tumor antigens

Tumor antigens in DNA plasmid, viral vectors, or synthetic peptides

Where is melanoma frequently found in dogs?

Oral cavity

Also the skin, eyes, and digits

When is the canine melanoma vaccine used?

For treatment of dogs with stage II/III melanoma after local disease control has been achieved

What is the antigen target in canine melanoma vaccine?

Tyrosinase protein

What is tyrosinase protein?

A self protein involved in melanin production

It's overexpressed in melanoma

How does the canine melanoma vaccine target tyrosinase without causing the body to start attacking itself?

With the xenogeneic DNA immunization strategy

Human tyrosinase antigen is used instead of canine

How do tumors evade the immune system?

Loss of expression of tumor antigens, MHC-I, TAP

TUmor cells present antigens in a tolerogenic form

Tumor cells may induce anergy

Secretion of immunosuppressive cytokines

Antigen masking

Tumor heterogeneity

What is TAP?

Transporter associated with antigen processing

What happens when tumor cells present antigens in a tolerogenic form?

There is a depressed or lack of co-stimulatory molecules

What happens when tumor cells induce anergy?

They produce PD-L1 and PD-L3 that bind to death receptors on T cells

What are immunosuppressive cytokines?

IL-10, TGF-beta

How do tumor cells mask antigens?

Increased glycosylation

Covers the antigem with glucose so it can't be recognized

What are diagnostic tests used to detect tumors?

Imaging

Biopsy and cytologic evaluation of cells

Serology for tumor-specific biomarkers

Immuno-phenotyping

Molecular testing like PCR

What imaging can be used to detect tumors?

O-rays, CT scan, MRIs, etc.