Cancer and the Immune System Flashcards
what are tumors/neoplasms?
cells that have lost control of the cell cycle
what are the two types of tumors/neoplasms?
- benign: unable to invade healthy surrounding tissue, incapable of indefinite growth
- malignant: becomes progressively more invasive and may metastasize
what are the three types of hematological system cancers?
- leukemia
- lymphoma
- myeloma
what causes leukemia?
cells of myogenous or lymphocytic origin in early stage of development in bone marrow
what causes lymphoma?
blood cells in their later stage of development outside the bone marrow spread through lymphatics to lymph nodes
what causes myeloma?
full differentiated plasma cells that mutated, produce antibodies, migrate back to bone marrow and form multiple lesions
how can a malignant transformation of cells be induced?
- chemical substances
- physical agents
- ionizing radiation
- viruses/infectious agents
- genetic predispositions
what are the two ways malignant cell transformations can occur?
through DNA alterations or cancer-associated genes
what are the three cancer-associated genes and how do they cause cancer?
- proto-oncogenes: genes that induce cellular proliferation become unregulated and cause uncontrolled cell growth
- tumor-supressor genes: inhibitors of cell proliferation (pro-apoptotic) mutates and allows cancer cells to survive when they fail
- apoptosis gene problem: abnormal cell survival
how can inflammatory responses promote cancer?
because chronic inflammation
- increases cellular stress signals
- lead to genotoxic stress
- increase mutation rates
- growth factors/ cytokines released by cells often induce proliferation
- inflammation is proangiogenic
what are the two types of tumor antigens?
- tumor-specific antigens
- tumor-associated antigens
what are tumor specific antigens?
unique to cancer cells, not found on normal cells, that arise due to genetic mutations or viral infections that create new, abnormal proteins where the immune system can recognize them as non-self and attack them.
what are tumor associated antigens?
Not unique to cancer cells—these are normal proteins but are expressed abnormally in tumors that are normally present during fetal development but reappear in cancer or proteins usually present at low levels but over expressed in tumors
what are some examples of tumor specific antigens?
Viral
- HPV: L1, E6, E7 - causes cervical carcinoma
- HBV: HBsAg - causes hepatocellular carcinoma
what are some examples of tumor-associated antigens?
Over expression
- HER-2/neu - causes breast, melanoma, ovarian, gastric and pancreatic
- PSA - prostate
- PAP - prostate
Differentiation Stage
- CEA - colon
- AFP - Hepatocellular carcinoma
why is the immune response (immunoediting) to cancer considered a double edged sword?
the immune system both protects against tumor growth and shapes the evolution of cancer cells. It consists of three phases
what are the three phases and the outcome of immunoediting?
- elimination: attacking the cells that can be targeted
- equilibrium: state of balance between destruction/survival of “best” cells
- escape: most aggressive/least immunogenic cells thrive and spread
- outcome: anti-tumor responses select for toughest cells
what are the innate cells that mediate tumor elimination and how?
- NK cells
- M1 macrophages: activated macrophages secrete TNF (strong anti-tumor activity) and bind to antibody coated tumor cells
- eosinophils: role not completely established yet
what are the adaptive cells that mediate tumor elimination and how?
- T cells
- Tumor-infiltrating lymphocytes: combination of T cells, NKT cells and NK cells
- B cells: generate anti-tumor antibodies against tumor specific antigens
how do NK cells regulate innate/adaptive cancer immunity?
cytokine secretion
explain the process of activation for a NK cell?
- cell is missing MHC 1 molecule
- cell is turned on through immunoreceptor tyrosine based activation motifs (ITAMS)
- phosphorylation of protein tyrosine kinases
- production of INF gamma and increase in IL-2 receptors
- lytic machinery
explain the process of no activation for a NK cell?
- inhibitory receptors bind to MHC class 1 molecules
- immunoreceptor tyrosine based inhibitory motifs are activated
- recruitment of phosphatases
- removal of phosphate groups (no protein tyrosine kinase activation)
how do NK cells recognize a target?
- inhibitory NK receptors (KIR3DL1) that binds to ligand MHC
- activating NK receptors (NKG2D): that bind to ligand, NKG2DL = MICA
what is MICA?
- MICA stands for MHC Class I-related chain expressed in various tumors
- It is expressed on melanomaand is an NKG2D ligand for the activation of NK cells
what are the 3 other activation mechanisms for NK cells?
- ADCC: NK cells express FcγRIII (CD16) , which is a receptor for the Fc region of IgG antibodies that causes cytolysis
- DAMPS: NK cells express NKG2D, an activating receptor that recognizes DAMPs on stressed or abnormal cells
- DEATH RECEPTORS: Fas cell death
receptor (CD95), and TNF-relatedapoptosis-
inducing ligand receptor (TRAILR) induce the
process of cell death when ligands that are released by NK cells bind
what is the mechanism of leathal hit used by CTL and NK cells?
- recognition
- adhesion and formation of conjugates
- transient calcium influx
- rearrangement of the cytoskeleton
- polarization of granules, golgi and microtubule organization center
- exocytosis of granules
- apoptosis (perforin mediated for CTL or FasL/Fas pathway for NK cells)
how do perforins and granzymes cooperatively cause apoptosis?
- perforin molecules polymerize and insert into the target cell membrane, forming pores or channels.
- pores allow the entry of granzymes and other molecules into the target cell
what is a granzyme and what do they do?
a family of structurally related serine proteases stored in cytotoxic granules
- Granzyme A induces loss of mitochondrial inner membrane potential, the release of
reactive oxygen species (ROS), and generates nicks in DNA strands.
- Granzyme B activates caspases.
what happens once granzyme B activates the caspases?
- leads cells to die of apoptosis
- FasL/Fas pathway can also mediate apoptosis.
what do NKT cells recognize?
- lipid-containing molecules, α-galactosylceramide(α-GalCer), on cancer cells
what are the two subsets of NKT cells that cross-regulate eachother?
- Type I NKT cells - promote anti-tumor immunity
- Type II NKT cells - suppress tumor immunity
how do type 1 NKT cells promote anti-tumor immunity?
- Produce IFNγ to induce other effector cells downstream, especially NK cells and CD8+T cells
- Activate DCs to make IL-12 and also be more effective in antigen-presentation
- Have lytic granules, perforin, and granzymes lyse a variety of tumor cells
what are the cytokines that fight cancer and how do they?
- IFN- γ - All interferon types enhance tumor cell removal activities of immune cells
- IL-12 - Encourages DCs to activate strong TH1 and CTL responses
- TNF-α may promote or inhibit anticancer effects; its role in cancer immunity is complex
what is involved with the evasion of immune elimination for immunosuppressive tumor microenvironments?
induction of suppressive cells
what are the suppressive cells that are located in the tumor areas?
- T reg cells
- Type II NKT cells that suppress tumor immunity
- suppressive macrophages
how do Type II NKT cells suppress tumor immunity?
- suppress immunosurveillance
- promote only regulatory cells including regulatory T cells and suppressive macrophages
what are examples of suppressive macrophages?
- tumor associated macrophages (TAM)
- alternatively activated macrophages (M2)
- myeloid derived suppressor cells (MDSCs)
what is one of the most immunosuppressive cytokines known and what cell secretes it?
- TGF-β
- myeloid derived suppressor cells (MDSCs)
what are examples of soluble factors that suppress immunity?
- TGF-β
- IL-10
- Indoleamine-2,3-dioxygenase (IDO)
how does IDO suppress immunity?
– allows tumor cells to escape - deplete tryptophan and generate kynurenine, promotes the generation of cells and is toxic to T cells and NK cells
how do tumors evade immunity by co-inhibitory signals?
- tumors may express inhibitory second signal molecules (PD-L1) that turn off / exhaust the T cells
why are antitumor antibodies NOT always GOOD?
- Antibodies may bind and block tumor antigens that CTLs would otherwise target
- Antibodies may form complexes with shed tumor antigens
- The complexes can impair the anti-tumor activities of NK cells and macrophages, which carry Fc receptors for ADCC and opsonization
what are the four loosely organized drug therapies for cancer?
- chemotherapies: aimed to block DNA synthesis and cell division
- hormonal therapies: interfere with tumor cell growth
- targeted therapies: small molecule inhibitors of cancer
- immunotherapies: induce or enhance the anti-tumor immune response
what are the 5 types of cancer immunotherapies?
- monoclonal antibodies
- adoptively transferred, antigen loaded dendritic cells
- adoptively transferred T cells
- engineered T cells
- immune checkpoint therapy
explain how toxin-conjugated monoclonal antibodies work?
a toxic molecule is chemically attached (or conjugated) to a monoclonal antibody that is designed to specifically target a tumor antigen which allows the toxic molecule to be delivered directly to the tumor cells
what is an example of a toxic molecule that is conjugated with a monoclonal antibody in cancer immunotherapy?
ricin
what are some successes of toxic-conjugated monoclonal antibodies?
- mAb against HER2 receptor in breast cancer
- mAb against CD20 B-cell marker (Rituximab)
for non-Hodgkin’s lymphoma - anti-idiotype mAb for terminal B-cell lymphoma
what is the goal of cancer vaccines?
enhance the anti-tumor immune response
how are cancer vaccines created?
- cultures patient DCs with cancer antigens and enhances antigen presentation with myeloid cell stimulation using GM-CSF
- the “Primed” DCs are reinfused to activate T cells
- the provoked CD4 T helper and CD8 CTL recognize and kill tumor cells
what is tumor-infiltrating lymphocyte therapy?
cells called Lymphokine Activated Killers (LAK) are derived from natural killer (NK) cells or T-cells and are activated and expanded using IL-2 cytokine in the laboratory (ex vivo) to enhance their ability to target and destroy cancer cells
what is CAR-T cell therapy?
CAR stands for Chimeric Antigen Receptor, a combination of parts from BCR and TCR that allows T-cells to recognize and attack cancer cells without needing antigen presentation
when is CAR-T cell therapy used and how does it work?
- used for patients with few treatment options, primarily for leukemia, lymphoma, and myeloma.
- The B part, VH and VL, recognizes tumor
- The T part, CD3-zeta signaling domains receptor activates the T-cell to attack the tumor
what is the process for making CAR-T cells?
- Harvest the patient’s T-cells
- Use a lentivirus vector to insert the CAR gene into T-cells
- Modify T-cells are then reinfused into the patient to target and kill cancer cells
what is the benefit of CAR-T cell therapy?
No need for MHC matching, allows sustained T-cell activation and tumor destruction.
what are the 3 generations of CAR-T cells?
First generation: Simple design with only activation signals.
Second generation: Adds dual signaling (e.g., CD28) for better T-cell activation, growth, and survival.
Third generation: Includes multiple signaling (e.g., OX40, CD137) to boost T-cell persistence and anti-tumor activity.
what are the side effects of CAR-T cell therapy?
- Cytokine release syndrome: An overactive immune response can lead to excessive inflammation
- Neurotoxicity: caused by inflammation
what is the purpose of Immune checkpoint therapy and what does it target?
- Decrease immune suppressive mechanisms and enhance anti-tumor responses in the tumor microenvironment
- Targets regulatory pathways (checkpoints) in T cells
what are two checkpoint antibodies used for immune checkpoint therapy?
- Anti-CTLA-4
- Anti-PD-1s
what is a side effect of checkpoint therapies?
The patient receiving the therapy frequently suffers from immune-related adverse events such as dermatologic, gastrointestinal, endocrine, or hepaticautoimmunereactions.
