intro to the TME and immune system Flashcards
differences in tissues of every organ
although we have these 4 different tissue types every organ is different
- , this is done by having different cells present, different cell Arrangement, different structures, oxygen levels sugar glucose lipids ,the availability of pH
- And then therefore the signaling between these different cells also Alters all of the above
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So if we’ve got a different type of cell present the signals that it can give out will alter the cells that are surrounding it. So not just the cells that are touching each other But the cells that are in the proximal area
TME is not simple or clear
for everything that is said about the TME there will always be the caveat we know it in this cancer or from this model or a cancer located in that organ, there are far more expectations to the models/ rules that in the intracellular drivers of cancer
how much of that definition of cancer is not actually intracellular. So not actually based on the mutations to the genetic changes in cancer.
- cancer cells have escaped the normal limitations of external cue driven cell division
- have modified their local environment to excees the natural defined tissue borders
- forms a multicelular mass driven by a transformed cancer cell
- have mechanisms to survive immune surveillance and cell death
innate immune system
- the innate immune system arrived in our bodies earlier and evolved alongside us
○ we’ve got macrophages neutrophils dendritic cells, esinophil and basophils
○ these innate immune cells Do not require learning.
○ That doesn’t mean that they can’t be changed or taught. They don’t need to learn what has happened to the body they can respond but they don’t need a learned response.
adaptive immunity
- The Learned response comes from the adaptive immunity. So this is normally mediated by antibodies.
- antibodies recognize antigens
- antigens can be most substances that are organic. They can be altered lipids, They could be altered Sugar’s they could be altered proteins - anything that is not self
- antigens are made up on cells that are normally infected in the first instances
- they also recognize mutated proteins, which is important for cancer because mutations can cause extracellular or intracellular proteins to change their shape and therefore be recognised as foreign antigens and therefore antibodies Be generated towards them.
natural killer cells
○ They have the ability to be innate immunity. So they’re able to respond independently of any learning so they can recognize when a cell is damaged or has been infected
- and they can also be trained by antibodies to Target specific cells independent on whether they’re damaged
why can’t we catch cancer - experiment
in this experiment, we’ve got two mice of different genetic backgrounds
- one is a BALB/c the other is C57BL/6 and both of these mice are presented with a carcinogen And they will go on to generate tumors.
- Once they’ve generated their tumors. We can isolate their cells and inject them into different mice
- if we go into a sygeneic mouie So this is the same Mouse BALB/c They will grow tumors. If we put them however into an allogenic host in which case they’re still the same species, but they are not the same genetic background the tumors cannot grow.
- So the genetic similarity between individuals even of the same species has meant that their immune system has tailored itself to their own genetics.
- So your immune system is tailored for you And your genetic background
MHC class 1
MHC class 1 are important molecules when it comes to immunogenicity and cancer.
- MHC class 1 is expressed on all of your cells it is used to display cellular proteins or cellular components that are part of the regulatory system.
The way MHC class 1 gets loaded is complex but basically it loads up the proteins that live inside a cell and displays parts of them to passing cells
T cell and MHC class 1
So MHC class 1 is loaded up with a protein and if we have an activated T Cell which has a T-cell receptor.
- And if this T Cell receptor has been trained to recognize this protein or this antigen It will bind to MHC class 1, recognize that this particular protein means that this cell is damaged, in danger or infected or indeed cancer.
And this can lead to the activation of the T-cell which will lead to the targeting of the Antigen displaying cell to be targeted for apoptosis or T Cell derived death.
what is the problem with this recognition
the problem with that is most of your cells in a tumor Are normal or at least they are so normal that they will not be recognized by the immune system.
- the majority of mutations are going to be silent. They’re going to be in regions of the DNA that don’t actually encode anything or they’ll be making minor changes to proteins.
- Only certain mutations are going to be advantageous.
- If a mutation is negatively impacting a cell then it won’t grow to be the majority of the tumor
- if it’s advantageous It might stay and we end up with a lot of it
if it’s silent. They’ll be no Advantage either way.
can we take a mouse and train it on tumour cells - vaccines
if we take a mouse and we take irradiated tumor cells
- They themselves cannot grow and we take them from this tumor and we inject them into to a fully immune stable Mouse.
- We inject them in, we can train this mouse to then recognize the cells if they come in live.
- So if we then inject viable cells into the mouse that we’ve already trained to recognize irradiated tumor cells we will find that the host will reject this tumor.
- However, if we were in to inject a different type of cancer cells from a different line, that they had not been trained on, the same Mouse has not acquired cancer resistance, It has required recognition of this particular tumor cells.
- So in this way, we can envisage an area where we can take someone’s cancer, We can irradiate it, we can train them on it and we can hope to get a adaptive learned response
-So this mouse has now been trained to recognize these types of tumor cells.
this gives the idea of personalized cancer vaccines and they can come in many different flavors
autologous whole tumour lysates
in this case, what we’re doing is a whole tumor inoculation, so we’re not really enriching it for anything in particular that we want the immune system to respond to
○ we’re just taking the whole of the tumor mashing up the cells, destroying them, giving all of that content into the mouse in the hope that the immune system will pick up enough antigens to be able to amount this adaptive response.
how do cancer cells evade antigen presenting detection
one of the first things cancer cells can do is down-regulate MHC class 1.
○ So if they are lacking MHC class 1 and they don’t have a lot of it. They will be displaying less antigens
○ if they’re displaying less antigens the chances of a T-cell binding with its T Cell receptor to an antigen is that much lower.
good and bad bits of the immune system when it comes to cancer growth
- It has tumour supportive cells and It has tumor suppressive cells
- T cells on their whole are tumor suppressive cells.
- If we were to look at different macrophages, so M1 or tumor Associated macrophages, these are two different flavors of macrophages
○ Some are tumour suppressive, some are tumour supportive - dendritic cells are tumour suppressive
natural killer cells are tumour suppressive.
we have different branches of the immune system
- some support tumor growth and some that suppressed tumor growth
- and it is about altering that balance with which immunotherapies are interested in
- they want to shift the balance to tumour suppressive cell types away from the tumor supportive cells
M1 macrophages
- M1 is anti-tumor - It expresses immunosuppressive cytokine
○ they secrete things like il-1 and tnf-alpha
○ these cells are far more likely to be cell lytic. They will bind to and cause phagocytosis
○ They are going to produce reactive oxygen species in order to cause damage.
○ These are the sorts of macrophages that in the normal scenario would be responding to a bacterial infection or a viral infection.
○ They would be the ones that arrived first
○ they can get activated by interferon Gamma which is produced normally by virally infected cells.
○ So macrophages that get stimulated by LPS or interferon-gamma become these immuno aggressive cell lytic ros expressing phenotype
