MSI Cancer Immunology Flashcards
Hallmarks of cancer include: Sustaining proliferative signalling Evading growth suppressors Activating invasion and metastasis Enabling replicative \_\_\_\_\_\_\_\_\_\_ Inducing angiogenesis Resisting cell death
immortality
The development of _______ of self-antigens can result in shielding of tumours from the immune system
tolerance
The two most important cells that illicit and anti-tumour effect are the ____ cells (which kills cancer cells by secreting perforin and granzymes?) followed by the ___ cells which multiply and signal other parts of the immune system to come to the site of disease via cytokines. This leads to cell death by recruitment of further NK cells and T cells
NK cells, T cells
The appearance of _____ Tumour infiltrating lymphocytes (TILs) in tumour, blood or lymph nodes usually suggests good prognosis in humans
CD8
The presence of _____ cells in tumours is a predictor of reduced survival
Treg
Higher incidence of cancer after immunosuppression, in immunodeficiency (AIDS) and _______
aging
Patients with SCID have _____ deficiency, which subsequently lead to tumour development (in mouse studies)
Rag
** Introduction of ___ (which is very immunogenic) into the bladder activates the immune system and results in targeting and killing of the cancer cells, with little effect on healthy cells
BCG
2 types of tumour antigens have been identified on tumour cells:
Tumour-associated antigens (TAAs)
Tumour-specific antigens (TSAs)
NOT unique to tumour cells and may be proteins that are expressed during foetal development
antigens normally expressed only at certain stages of differentiation
may also be proteins that are expressed only at very low levels on normal cells, but overexpressed in particular tumours
describes which type of tumor antigen?
Tumour-associated transplantation antigens (TATAs)
OR Tumour-associated antigens (TAAs)
Unique to tumour cells and are not present on normal body cells
antigens encoded by genes specifically expressed by tumours (example is a p53 mutation)
antigens encoded by variant forms of mutated genes
describes which type of tumor antigen?
Tumour-specific transplantation antigens (TSTAs)
OR Tumour-specific antigens (TSAs)
Tumour-associated transplantation Ag- mutation generates new peptide in class I MHC molecule. Also known as
neoantigens
Overexpression of a normal protein represents which time of tumor antigen?
Tumour-associated transplantation antigens (TATAs)
Inappropriate expression of embryonic gene represents what type of tumour antigen?
Tumour-associated transplantation antigens (TATAs)
If a mutation generates a new peptide in class I MHC molecule, this represents what type of tumour antigen?
Tumour-specific transplantation antigens (TSTAs) (also known as neoantigens)
Know that there are different types of tumour antigens that have potential consequences for cancer therapies:
Tissue differentiation Ags (TAA),
tumour germline “tumour-testis” Ags (TAA),
normal proteins overexpressed by cancer cells (TAA), Viral proteins (TSA),
or tumour-mutated Ags (TSA)
Note that tumour germline antigens are not recognized in the ________, as those cells do not express Class I MHC.
testis
Examples of tumour-specific mutated antigens (only expressed in tumour cells as a result of mutation):
Ras, p53
Innate responses to tumours(not MHC restricted):
_________ cells
Can kill directly tumour cells, helped by interferon-alpha and -beta and IL-2
Macrophages
Can infiltrate tumour masses; known as tumour-associated macrophages (TAMs). Can be pro-
tumourigenic or anti-tumourigenic.
Natural killer (NK)
Adaptive responses to tumours (T cell responses are MHC restricted)
________ T-cells
Can directly kill tumour cells via tumour antigen recognition
T helper cells
Produce a variety of cytokines that activate other types of immune cell
e.g. Interferon-gamma & TNF (macrophages); IL-2 (CD8+ T cells and NK cells)
B cells
Production of tumour-specific antibodies (may be functional or not)
Cytotoxic
CD8 T cell activated by specific antigen presented by APC plus co-stimulation via ______/CD86 molecules
Activation results in production of IL-2 which drives proliferation
CD80
In-built mechanisms of control of T cell responses:
Inhibitory receptors expressed by T cells – these interfere with co-stimulatory signalling
Examples are:
CTLA-4 (during activation): ligand is ___ molecules
PD-1 (during effector function): ligand is PD-L1
FAS: ligand is FASL
B7
CTLA-4 binds B7 more avidly than does CD28 and delivers __________ signals to activated T cells
inhibitory
A tumour mass consists of:
a heterogeneous population of cancer cells with varying degrees of mutation
a variety of resident and infiltrating host cells
secreted factors and extracellular matrix proteins
This is collectively known as the
tumour microenvironment.
The tumour micro-environment refers to the normal cells, molecules, and ___________that surround and feed tumour cells.
blood vessels
Factors such as TGF-beta, PD-L1 secreted by tumour cells can _____ T cells directly
inhibit
Cytotoxic T cells refer to CD8+ T cells that have been activated via recognition of specific antigen presented on MHC ________ – also known as CTLs.
Class I
The immune system can recognize cancer cells
Most relevant immune responses mediated by NK cells and ______ T cells
Recognition by immune cells can occur via altered cell surface molecules or via tumour antigens
cytotoxic
the immune system’s ability to recognize and destroy emerging cancer cells
Cancer immunosurveillance
Theory that describes how the immune system can kill cancer cells; but can also induce changes in the tumour resulting in tumour cell escape and further growth of tumour mass (by epigenetic changes or Darwinian selection)
Cancer immunoediting theory
What are the “3 E’s” of cancer immunoediting?
Elimination, equilibrium, escape
One way that tumour cells “escape” from T cell recognition is via loss of _______
MHC I
Some tumour cells develop into cells that express very low (or none) levels of MHC Class I and these cells are not recognized by cytotoxic T cells so can survive and proliferate = _______ phase
Escape
Some tumour cells develop into cells that express only moderate levels of MHC Class I and so survive for longer than those expressing higher levels, but are eventually killed by cytotoxic T cells (4). As these moderately MHC expressing cells survive longer before being killed, they have longer to proliferate and so generate new cancer cells before eventually being killed = ___________ phase of the 3Es model where the tumour mass is in dynamic equilibrium with the immune system.
Equilibrium
The tumour cells express MHC Class I on their surface at normal levels and present tumour antigens via these MHC molecules which are recognised by cytotoxic T cells.
Some of the tumour cells develop into cells expressing higher levels of MCH Class I molecules and so are recognised and killed by cytotoxic T cells faster than other cells in the tumour. This killing of these tumour cells may reduce the size of the tumour mass = ____________ phase of the 3Es model.
Elimination
** Mechanisms of tumour escape:
Reduced levels or absence of MHC I molecules on tumour so that they can not be recognized by cytotoxic T cells
Some tumours stop expressing the antigens recognized by immune system
These tumours are called “_____ ______ ______”
Production of immunosuppressive factors by tumor e.g. transforming growth factor (TGF-β), PD-1 ligand (PD-L1)
antigen loss variants
Tumour evasion mechanisms of the immune system:
Low immunogenicity (Low/absent MHC 1): No peptide: MHC ligand, no adhesion molecules, no co-stimulatory molecules
Antigenic __________ (Ag-loss variants)- Ab against tumour cell-surface Ags can induce endocytosis and degradation of the Ag. Immune selection of Ag-loss variants.
Tumour-induced immune suppression (direct suppression of CTLs)- Factors such as TGF-beta and PD-L1 secreted by tumour cells inhibit cells directly
modulation
Homeostatic mechanisms aimed at preventing excessive inflammation and tissue damage
Immunological checkpoints.
Immune checkpoints prevent the immune response from completely eliminating the pathogen or destroying the tumour.
What is a CAR-T cell?
Chimeric antigen receptors which have been engineered to graft an arbitary specificity to an effector cell (T cell)
CARs include three parts: an extracellular antigen recognition domain of the single-chain Fragment variant (scFv) derived from an antibody), a transmembrane domain and an intracellular T cell activation domain of CD3ζ
How are the CAR-Ts introduced?’
Two ways to accomplish gene incorporation with vectors:
Viral and Non-viral
How do CAR-T’s work?’
works by triggering the immune system to recognize tumours and thus activates cancer cell lysis
Structure of a CAR-T
ScFv -an antibody fragment replacing the TCR which will recognize the tumor associate antigen (TAA)
___ is the signaling domain that will activate the immune response once the antigen bind to the scFv
CD3
Side effects of immunotherapies
Complicated by severe immunosuppression/ cytokine release syndromes
Immune evasion mechanisms by tumours include reduced tumour antigen presentation and local immunoregulatory factors: inhibitory ________ and cells
cytokines
