Bu it is worth asking a question: why bother with the candidate list at all? Can’t we just be maximalist about it and stuff thousands of candidates into the vaccine? It only takes one (or maybe a few) to hit. It’s not like there are any downsides to being aggressive here.
Sadly, there is a downside to being aggressive.
Namely, a concept called “immunodominance”, which is the observation that when you present the immune system with a mixture of antigens, the resulting T-cell response tends to concentrate on one or a small handful of “winners,” with the remaining antigens getting ignored or generating responses so weak they might as well not be there.
I am confused: aren’t the T cells already exposed to all the neoantigens anyway ? Or we are wrapping the neoantigens into an adjuvant that will tell them they are dangerous, and immunodominance happens when the adjuvant wraps many peptides at once ? I guess this is it but since all my oncology knowledge is basically this post, I’m not sure
Also, since all the peptides that we are showing them are produced by cancer cells, why is it so bad that the T-cells “pick a handful” of winners ? Since the winners will point them to cancerous cells anyway
aren’t the T cells already exposed to all the neoantigens anyway ?
Yes, but they have also been immunosuppressed for long enough (by the cancer) that they often just are either too ‘exhausted’ to care about the neoantigens, or are actively discouraging one another to care. Adjuvants help encourage them to take a second look at a very specific biomolecule, and immune checkpoint inhibitors allow them to do so. I’m obviously anthropomorphizing things a bit; the processes here are complicated and badly understood.
immunodominance happens when the adjuvant wraps many peptides at once
Hmm, it’s more general than that. You can think of immunodominance as a triaging decision made by your immune system. It cannot mount maximal T-cell responses to every antigen it sees, because that would be both energetically costly and immunologically dangerous, so it just gambles on maximizing response to few antigens. This isn’t too big of a deal for viruses, because any one of a viruses antigens are probably genuinely enough to mount a useful immune response. Not so true for cancer!
Also, since all the peptides that we are showing them are produced by cancer cells, why is it so bad that the T-cells “pick a handful” of winners ? Since the winners will point them to cancerous cells anyway
Because the winners may not be pointing to cancerous cells! Unless you actually verified that the peptides are presented by cancer cells via immunopeptidomics methods, which is practically rarely (if ever) done.
I am confused: aren’t the T cells already exposed to all the neoantigens anyway ? Or we are wrapping the neoantigens into an adjuvant that will tell them they are dangerous, and immunodominance happens when the adjuvant wraps many peptides at once ? I guess this is it but since all my oncology knowledge is basically this post, I’m not sure
Also, since all the peptides that we are showing them are produced by cancer cells, why is it so bad that the T-cells “pick a handful” of winners ? Since the winners will point them to cancerous cells anyway
Great questions!
Yes, but they have also been immunosuppressed for long enough (by the cancer) that they often just are either too ‘exhausted’ to care about the neoantigens, or are actively discouraging one another to care. Adjuvants help encourage them to take a second look at a very specific biomolecule, and immune checkpoint inhibitors allow them to do so. I’m obviously anthropomorphizing things a bit; the processes here are complicated and badly understood.
Hmm, it’s more general than that. You can think of immunodominance as a triaging decision made by your immune system. It cannot mount maximal T-cell responses to every antigen it sees, because that would be both energetically costly and immunologically dangerous, so it just gambles on maximizing response to few antigens. This isn’t too big of a deal for viruses, because any one of a viruses antigens are probably genuinely enough to mount a useful immune response. Not so true for cancer!
Because the winners may not be pointing to cancerous cells! Unless you actually verified that the peptides are presented by cancer cells via immunopeptidomics methods, which is practically rarely (if ever) done.
Thank you! That makes things more clear to me.
Thank you also in a more general way for putting out accessible articles on these topics, I really enjoy learning from them