Unit 5- Tumor Immunology/ Immunotherapy Flashcards
What is central T cell tolerance?
- immature T-cells move from bone marrow > thymus for maturation
- eliminate any autoreactive lymphocytes (discriminate self vs non-self)
- test for autoreactivity
3 outcomes- interaction of immature T cells/ self MHC antigens thymus
Non-Selection- no interaction > apoptosis
Positive Selection- binding > survival/ maturation of T cells
Negative Selection- strong affinity > apoptosis
What is peripheral T-cell tolerance?
self-reactive T cells > anergy/ apoptosis/ suppression
What is the difference between cytokines/ chemokines?
Cytokines- chemical messengers
Chemokines- chemoattractants
What is the cancer immunoediting hypothesis?
- describes the role of the immune system in tumorigenesis
The 3 E’s: Elimination/ Equilibrium/ Escape
What is the elimination phase of immunoediting?
- cancer immunosurveillance
- innate/ adaptive immunity detects tumors before clinically visible
- tumor antigen presentation to T cells > T cell cytotoxicity
How does tumor antigen presentation to T cells/ T cell cytotoxicity work?
- professional APC’S (dendritic cells/ macrophages/ B cells) take up tumor antigen/cross-present peptide via MHC
- TCR recognizes tumor antigen on APC > inflammatory cytokines
What are the requirements of T cell-mediated killing of tumors?
- ability of tumor to present tumor antigens via MHC-1
- tumor not overexpressing T cell inhibitory ligands (PD-L1)
- functional state of cytotoxic T cell
What is the equilibrium phase of immunoediting?
- immune system holds tumor in a state of functional dormancy
- tumor cells undergo changes due to immune pressure
> immune evasion/ induce immunosuppression
“survival of the fittest”
What is the escape phase of immunoediting?
- immune system fails to restrict tumor growth > clinically apparent disease
- tumor cells evade immune evasion/ inhibit T-cell killing
What is the difference between hot/ cold tumors?
Hot tumors- immune cell infiltration/ respond well to immunotherapy
Cold tumors: do not respond to immunotherapy
-T cell Exclusion > successful antigen presentation, no killing
-T cell Desertification > no antigen presentation to T cells
What are immunogenic cell death inducers?
- cell death that can activate antitumor immunity
> chemotherapy/ radiation - hard to measure biomarkers in patients > barrier to clinic evaluation
What is cytokine-based cancer therapy?
- systemic/ intratumoral administration of a proinflammatory cytokine
- modulates entire immune response to anti-tumor
ex) IL-2 - rapid T-cell expansion/ side effects now manageable
What is immune checkpoint blockade (ICB)?
- use of immune checkpoint inhibitors (ICIs)
- immune checkpoints serve as brakes on T cells
- blocking inhibitory immune checkpoints with monoclonal antibodies unleashes T cells to exert cytotoxic effects
- combination therapy to make cold tumors hot
> immunogenic tumor microenvironment - off-target immune adverse effects
- any immunogenic peptide can be targeted
What is antibody-based therapy? (non-immune checkpoint related)
ADC = Antibody Drug Conjugates
3 components: antibody/ linker/ payload (cytotoxic drug)
- deliver effective cytotoxic chemo drug specifically to tumor
Tumor Resistance- loss of tumor antigen/ resistance to payload
- side effects of normal chemo
What are the 4 main types of cancer vaccines?
- fail against metastasis
Cell-based- 1 approved > monocyte/dendritic cells
Viral-based- tumor antigen in viral particle
Peptide-based
Nucleic acid-based- mRNA vaccines > faster/ easier to make
What is oncolytic viral therapy?
- oncolytic virus exploits tumor > selective virus replication
What is the mechanism of action of oncolytic viruses?
- Direct killing of tumor cells
- Tumor vascular shutdown (↑ hypoxia/ ↓ vasculature)
- Activate immune response against cancer
What is the result of oncolytic virus infection?
healthy cell > viral clearance/ no effect
tumor cell > lysis > inflammation/ release of viral progeny > infection of neighbouring tumor cells/ tumor antigen release > systemic anti-tumor response
How are tumors/ oncolytic viruses a match made in heaven?
Tumor- ↑ virus receptor expression/ loss of innate antiviral responses
OV > selective/ unrestrained virus replication in tumor cells
What is CARS?
Chimeric Antigen Receptor Based Therapy
- combination of monoclonal antibody (antigen recognition)/ TCR (signal transduction)
- chimeric antigen receptor triggers TCR signaling in cell
- patient T cells engineered with lentivirus > deliver CAR-encoding gene
- deplete bone marrow with chemo to make room for T cells
- CAR T-ells reinfused into patients blood
- CAR T cells identify cancer cells/ kill them
What are side effects of CAR-T cell therapy?
On-target/off-tumor toxicity > target normal B cells > B cell aplasia
Cytokine release syndrome > neurological toxicity/ confusion/ fever
- CAR-T product can last for years after infusion/ great success in blood cancers
What is TIL therapy?
Tumor Infiltrating lymphocyte therapies
- similar to CAR-T therapy but no engineering
- expansion of patients T cells, still deplete bone marrow with chemo
- ↑ success in solid tumors compared to CAR-T
- tumor harvest/ liberate TIL from TME/ select based on reactvity/ ex vivo expansion/
