tumor immunology Flashcards
Tumor Associated Antigens
Distinguish neoplastic cells from normal cells
Examples
* Altered proteins due to genetic mutations
* Excessive production of normal proteins
* Viral proteins (if tumor was caused by a virus)
* Expression of proteins not typical for the cell type (de-repression)
Natural Killer cells
Part of the innate immune system
Activated by an imbalance between stimulatory and inhibitory signals
* Foreign antigens = stimulatory signal
* Loss of self MHC I = loss of inhibitory signal
Activation – release of cytoplasmic granules that cause cell lysis (Perforin, Granzyme)
Also secrete IFN-gamma which has direct and indirect anti-tumor activities
adaptive immune response to tumors
Antigen presenting cells stimulate CD4 Th1
CD4+ Th1 cells Release IFN g to stim CD8+ Tc cells
Stages of immune response to tumor
- Elimination: All abnormal cells are destroyed
- Equilibrium: Cells resistant to immune response = cells destroyed
- Escape: Cells resistant to immune response > cells destroyed
Mechanisms of tumor immune system invasion
Decreased expression of tumor antigens
Decreased expression of MHC proteins
Decreased co-stimulatory signals
lymphocyte neoplasia
lymphoma
plasma cell neoplasia
plasma cell tumor
macrophage/APC neoplasia
cutaneous histiocytoma
myeloblast neoplasia
myeloid leukemia
mast cell tumors
Canine Cutaneous Histiocytoma
Tumor derived from dendritic cells (APCs)
Common on head, ears, muzzle and legs of young dogs
Characterized by tumor-infiltrating Tc cells
Often spontaneously regress
Inflammation-Associated Neoplasia
Mechanisms
* Inflammatory mediators damage DNA
* Inflammation can inhibit apoptosis
* Effects of tumor associated macrophages and regulatory T cells
Examples
* Inflammatory bowel disease and alimentary lymphoma in dogs and cats
* Vaccine-associated sarcoma in cats
Inflammation-Associated Neoplasia
Mechanisms
* Inflammatory mediators damage DNA
* Inflammation can inhibit apoptosis
* Effects of tumor associated macrophages and regulatory T cells
Examples
* Inflammatory bowel disease and alimentary lymphoma in dogs and cats
* Vaccine-associated sarcoma in cats
Pro tumor effects of immune system
Tumor-associated macrophages
* Infiltrate tumors
* Secrete factor that can promote tumor growth and metastasis
* Metalloproteinases – enzymes that degrade extracellular matrix
* Vascular endothelial growth factor – promotes vessel growth
* IL-10 – immunosuppressive cytokine
Regulatory T cells
* Inhibit NK and Tc cells
Paraneoplastic Syndromes
Definition – remote or systemic changes associated with a neoplasm
May be the first indication of cancer
Usually secondary to products of tumor or immune system cells
Most common in veterinary medicine:
* Hypercalcemia
* Hypoglycemia
* Anemia
* Cachexia
Paraneoplastic hypercalcemia
Cancer is the most common cause of hypercalcemia in companion animals
* Anal sac apocrine gland adenocarcinoma – tumor produces parathyroid hormone related peptide
* T-cell lymphoma - osteolysis
* Also, multiple myeloma, thyroid carcinoma, osteolytic bone tumors
Paraneoplastic Hypoglycemia
Glucose utilization by neoplastic cells
Decreased glycogenolysis and gluconeogenesis
Production of insulin-like growth factor
Tumor types
* Insulinoma – excess insulin production
* Hepatocellular carcinoma
* Hemangiosarcoma
* Melanoma
* Lymphoma
* Multiple myeloma
Paraneoplastic Anemia
Anemia of chronic disease – decreased iron metabolism and storage
IMHA – Cross reaction between tumor antibodies and erythrocyte surface antigens
Blood-loss anemia – gastrointestinal/urinary tumors, hemangiosarcoma
Bone marrow disease – lymphoma or leukemia replacing hematopoietic cells in the bone marrow
Kidney Tumor: decreased EPO
Cancer Cachexia
Progressive wasting with loss of skeletal muscle and adipose tissue (mostly skel muscle)
Not completely explained by decreased food consumption
50% of cancer patients
Tumors of gastrointestinal tract and lung
Multifactorial
Inflammatory cytokines are an important component
* TNF alpha
* IL-1
* IL-6
Cancer Treatment
Surgery – remove the tumor
Chemotherapy – disrupt cell division or target tumor cells with chemicals
Radiotherapy – disrupt cell division with radiation
Immunotherapy:
* Tumor non-specific – promote innate immune response
* Tumor specific – promote adaptive immune response
Tumor Non-Specific Immunotherapy
Macrophage and monocyte activators
* Pattern recognition receptor agonists (MTP for canine osteosarcoma)
* Intratumoral injection of antigens (Immunocidin for mammary tumors in dogs, Acemannan)
NK cell targeted therapy
* Cationic liposome-DNA complexes
* Recombinant cytokines (IFN alpha, IFN gamma, IL-12)
Manipulation of Tumor Microenvironment for treatment
Microenvironment = fibroblasts, endothelial cells, macrophages
Depletion of tumor associated macrophages
* Liposomal clodronate – in trials for sarcomas in dogs
Inhibition of macrophage migration into tumors
* Migration mediated by chemokine CCL2 binding to CCR2 receptor
* Block with CCR2 agonists
Tumor Vaccines
Vaccine types
* Whole tumor cells – lysed or irradiated (expensive, no mass production)
* Tumor antigen-specific vaccines (may select for cells that have lost the antigen)
One vaccine currently approved: Tyrosinase protein for melanoma in dogs (Oncept)
Obstacles
* Tumor associated macrophages suppress T cell response
* Regulatory T cells suppress T cell response
* Solution: Vaccine + TAM or Treg depletion
DONT know specifics
Adaptive Transfer of Modified T Cells
Collect patient’s CD8+ Tc cells (lymph node excision)
Expand the number in culture
Manipulate T cell to target the tumor
Transfect with genes for antibody receptor
Use bi-specific antibodies (bind tumor antigen and T cell)
Re-infuse the lymphocytes
Checkpoint Molecule Inhibitors
Checkpoint molecules – cell surface molecules that limit T cell proliferation (CTLA-4, PD-1, TIM3, Lag3) when bound to ligands
Blocking these molecules allows for more T cell production
Block with monoclonal antibodies
