Tumor Immunity Flashcards
List 3 peices of evidence that immune system can recognize tumor “altered self” antigens
- higher amount of T cell infiltration into tumor tissue correlates with a bettr prognosis
- tumor transplants are rejected by an animal already exposed to that tumor (adaptive immune memory mediated by T cells)
- Immunodeficient individuals have an incresaed incidence of some tumor types
What is the cancer immunoediting concept? there are 3 stages explain them
- Elimination
- Immune system is attacking the tumor
- Equilibrium
- the tumor begins to modify
- Escape
- the tumor evades the immune system and continues to grow
What is the escape phase?
- immune responses frequently fail to prevent tumor growth. the immune system is designed to prevent “self” reactivity, so mechanisms are in place to prevent immune reactivity to cancerous cells.
once we are in the escape phase and the tumor has evaded immune response are we doomed?
NO! there is hope. the immune system can be reactivated by external stimuli to kill tumor cells and elimate tumors
What are the cells that are a part of the adaptive immune system
- Helper th1 CD4 T cells- provide stimulatory cytokines (IL-2, IFN-y)
- Cytotoxic CD8 T cells- killer cells secrete granzyme (serine proteases) and perforin
- B cells- soluble anti-tumor IgG and IgM adn complement-mediated killing
How do T cells kill tumor cells if tumors are self?
- T cells are SELF-mutated, or SELF-overexpressed, non-self viral peptides
What are the 4 signals that are requierd to produce activated effective anti-tumor CD8 CTLs?
- Enaggement of TCR with MHC I presented tumor peptide on APC (DC, Macrophages, B cells)
- Engagement of co-stimulatory ligands CD80/86 (APC) with activating receptors CD28 (T)
- Effector/memeory cytokines (IFNy, IL-2, IL-5, IL-7, IFNab, IL-12)
- upregulation of chemokine receptors required for T cell traficking
once a T cell is activated does it require co-stimulation?
NO it is already active so its good to go
What cells in the innate immune system are involved in tumor elimination
- yDeltaT cells- recognize phosphoantigens expressed by tumor cells, are cytolytic and produce IFN-y and TNF-a. Express the gamma delta TCR not the classical alpha beta TCR
- NK- produce IFN-y, tumor cytolytic-liberate tumor antigens to DCs induce DC activation and maturation
- Dendritic Cells- secretion of Il-12 and type I IFNs and cross presentation of tumor antigen to CD8 T cells Immature DCs are tolerogenic
- Macrophages: M1: proinflammatory mediators, M2 protumorigenic
WHat cytokines are considered anti-tumor
- IFNy-activates macrophages, induces MHC class II, produced by activated NK and T cells
- IFNa and B-influene activation of innate and adpative immunity, viral
- IL-12L stimulates production of IFNy and TNF from T cells enhances cytotoxicity (self-amplify immune repsonse)
- TNF- acute phase inflammation
- NKG2D- stimulatory receptor, the ligand is overexpressed by infected, transformed, senescent and stressed cells
- TRAIL- death receptor ligand expressed on activated T cells
- Perforin-cytolic meiator produced by cytotoxic T cells
How do cancer tumors have a barrier to the immune system
- immune suppressive cell types
- intrinsic spressive T cell mechanisms
- immune inhibitory facotors in the tumor microenvironment
WHat cells are involved in tumors ability to inhibit the immune system
- Immature/tolerogenic DCs
- Myeloid suppressor cells
- M2 macrophages
- T Regulatory cells
- Th2 CD4 T cells
What is immunotherapy
mechanisms to ramp up T cell activation
antibodies that target tumor antigens resulting in tumor cell death
What are the 8 ways to ramp up the T cells
- Block the T cell inhibitory (checkpoint) receptors using blocking antibodies
- Adoptive transfer of tumor-specific T cells
- Gentically manipulate T cells for adoptive cell tranfer (chimeric antigen receptors of CAR T cells)
- Allogenic T cells for anti-leukemia effect
- Bispecific antibodies (direct T cell to target molecules)
- Agonist antibodies to co-stimulatory T cell receptorsL CD40, CD137, ICOS, CD28, OX40
- peptide, dendritic cell and DNA vaccines
- immune stimulatory agents
what are immune checkpoints and what do we use to block them
- a plethora of inhibitory pathways 9receptors/ligands) hardwired into the immune system (T lymphocytes, NK cells, B cells and others) to maintain self-tolerance and modulate the duration and magnitude of an immune response: cancers can co-opt these pathways to their advantage
- Monoclonal antibodies are used to interfere with immune suppression (block immune checkpoints)
- ex: CTLA-4 and PD-1
What are two immune inhibitors
CTLA-4 and PD-1
What cellular immunotherapy using TILs
- lymphocytes can be cultured from tumors by removing them in surgery.
- they are anti-tumor infiltrating lymphocytes
- TILs are expanded in culture and then give back to patients to provide large numbers of highly activated T cells that recognize cancer cells.
- this bypasses the suppressive mechanisms of the tumor
What are Chimeric Antigen Rceptors?
CAR T cells
- A modified T cell that expresses their native antigen receptors and are able to become strongly activated when the antibody portion of the receptor binds to its antigen
- don’t need co-stimulation
Allogenic T cells (Hematopoietic Stem Cell Transplantation) as Cancer Immunotherapy
Donor T cells that are transplanted to the host (patient) along with hematopoietic stem cell graft become activates to host alloantigens. While these activated donor T cells can attack host tissues and can cause graft-versus host disease (GVHD), they can also eliminate residual host cancer cells that express alloantigens
What is BiTE?
Bispecific antibodies- T cell Engagers BiTE
BiTE gross the T cell and the Tumor and brings them together so the T cell can kill it. It is a way to bypass APCs
what are agonist antibodies to co-stimulatory receptors
agonists to co-stimulatory receptors like CD40 and CD28. Help you get over needing co-stimulation. this isn’t that helpful though when you don’t have a lot of T-cells bc it wont’t make that big of an effect.
WHat are dendritic cell vaccine
incubate DCs with tumor antigens, or gentically modify DCs to express tumor antigens. then you inject the DCs. this can help bypass the need for endogenous APCs in the body.
What are DNA vaccines
DNA actiavtes the innate immune system. You encode the DNA so it encodes tumor antigen. you then inject this naked DNA that has tumor antigen into the patient and it is phagocytosed and the infor is presented by an APC and is a stimulant for T cell actiation
What are whole cell tumor vaccines
remove some tumor cells ans then irradiate them to stop growth. then modify the genes and inject the irradiated tumor cells back in to stimulate the immune system!
