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L12 - Tumor and immune system, take note: only DC, B cells and…
L12 - Tumor and immune system
immune system
innate immunity
present and ready to fight pathogens at site of infection
main immune cells involved in cancer destruction
macrophage
detection, phagocytosis of pathogens
present antigen to T cells
release cytokines to activate other cells
Natural killer cell (NK)
releases perforin, forming pores on the cancer cell
granzymes induce apoptosis
NK cells are able to recognize cells that downregulate MHC 1 (common in tumor cells), this leads to killing of cell
dendritic cell (DC)
act as messengers btwn innate and adaptive immune system
present antigen to T cells
endogenous antigens are digested by proteasome and presented on
MHC class 1.
exogenous antigens are presented on
MHC class 2
adaptive immunity
delayed reaction
gets stronger upon repeated exposure
humoral response
Antibody mediated response
involves B cells
activation of complement system
antibody binds to antigen of pathogen
activates complement system
forms membrane attack complex (MAC)
antibody dependent cellular cytotoxicity (ADCC)
antibodies bind to antigens on pathogen
NK cells recognizes Fc region of antibody
NK cells releases granzymes and perforins
leads to apoptosis of cell
opsonization (enhanced phagocytosis)
antibody binds to the antigen present on pathogens
macrophage recognizes and binds to the Fc region of antibody
neutralization
antibody binds to virus antigen
cellular response
APC present antigens to T cells
cytokines are released
activation of immune system
T cells
CD4+ T cells
T cell receptor binds to antigen presented on MHC class 2
B7 on APCs binds to CD28 on CD4+ cells
immature CD4+ T cell matures into T helper cells
IL-2 and IFN-gamma released by helper CD4+ T cells activate cytotoxic T cells
IL-10 and IL-4 enhances B cell proliferation and antibody production
CD8+ T cells
T cell receptor binds to antigen presented on MHC class 1
costimulatory molecules B7 and CD28 binds
immature CD8+ T cells matures into cytotoxic T cell
cancer and tumor cells
Tumor specific antigens (TSA)
are only found on tumor cells
amino acid sequence changes
protein formed will be different
triggering immune response
example: hyperactive Ras protein due to mutation continuously signals for transcription
tumor associated antigens
antigens are found on both normal and tumor cells
overexpression of antigens in tumor cells
example: HER2 receptors are expressed in large numbers on breast cancer cells, leading to more signals, cancer cells grow quickly
Detection of cancer and tumor cells
CD4+ helper T cells
recognizes antigen on MHC class 2
activated to release cytokines
dendritic cells
they take up tumor antigens and present on MHC class 2
Immunoediting
allows tumor progression
Equilibrium
equilibrium is the longest stage
tumor dormancy and editing
Escape
tumor can totally escape immune system
leads to tumor growth promotion
immunoevasion
repression of antigen presentation
reducing expression of MHC 1 on cell surface
reduction in antigen processing (antigen loss)
repression of NKG2D ligand
tumor cells are able to escape NK cells through reducing natural killer ligands (NKL) on cell surface that binds to the NKG2D on NK cells
inactivate immune cells
in normal cells, Treg cells are used to inhibit activation of naive T cells to regulate the immune system, preventing it from overreacting
in the tumor microenvironment, Treg cells increases
Treg expresses CTLA-4 which competitively binds to B7 as it has a higher affinity to B7 compared to CD28
forming co-inhibitory complex and will not allow T cell activation
this allows tumor cells to proliferate
induced immunocyte apoptosis
tumor cells produce FasL that will bind to the Fas on the surface of T cells, inducing apoptosis of T cells
production of immuno-suppressive cytokines
molecules secreted by tumor directly inhibits T cells
e.g TGF- beta (tumor growth factor), this triggers neighboring normal cells to die, allowing more space for tumor cells to grow
Elimination
tumor cells that are recognized by immune cells are eliminated/killed
immune system destroying cancer and tumor cells
B cell activation
B cells produce antibodies after activation by CD4+ helper T cells
antibodies bind to antigens on the tumor cell, this signals the NK cells to kill tumor cells through production of perforin and granzymes (ADCC)
antibodies trigger neutralization, opsonization and activation of complement system.
CD8+ T cell activation
cytokines released by CD4+ helper T cells proliferate cytotoxic T cells
T cell receptors recognizes tumor antigens on MHC class 1
tumor cells are destroyed either through perforins and granzymes or Fas and FasL
NOTE
: the cell that has the FasL is the cell doing the killing, FasL can be present on tumor cells as well.
cancer immunotherapy treatment
monoclonal antibodies
tumor-specific antibodies bind to the tumor cell
tumor-specific antibody conjugated to toxin (conjugates are internalized, killing the cell)
tumor-specific antibody conjugated to radionuclide
"naked" monoclonal antibodies (mAbs)
blocks specific target on the cancer cells
can also target around the area of cancer (e.g blood vessels)
blocks signal or receptor
example 1: checkpoint inhibitors
normal cells has PD-L1 which will bind to PD-1 on T cell which will inhibit the killing of the normal cell
however, presence of PD-L1 on tumor cell will also inhibit T cell killing the tumor cell.
therefore, we can design anti-PD-L1 and anti-PD-1 to block the respective sites. no interaction will take place between the molecules
T cells will then kill the tumor cell
disadvantage
: anti PD-L1 and PD-1 will also bind to normal cells, killing normal healthy cells as well
example 2: checkpoint inhibitors
CTLA-4/B7 binding will inhibit T cell activation
blocking CTLA-4 with anti CTLA-4 antibody will allow the killing of tumor cell
antibody-drug conjugates (ADCs)
antibody conjugated with anti-cancer drugs
antibody is specific to cancer cells
chemotherapeutic drugs will directly be delivered to cancer cell, reducing side effects
Bispecific T cell engagers (BiTEs)
targets both cancer cells and T cells
antibodies work to bring T cells closer to cancer cells enabling them to kill cancer cells
cell therapy :!:
cytokine therapy :!:
cancer vaccines :!:
take note:
only DC, B cells and macrophages have MHC 2
MHC 1 is present on all nucleated cells