As I’ve noted several times before, regulatory T cells are important reasons for the poor immune response to tumors. TRegs are normal components of an immune response, “designed” to keep inflammation from running riot in general and to prevent responses to self-antigens in particular. Whether it’s because tumors are mostly (though not solely) self antigens, because tumors are chronic sources of stimulation that could lead to inflammation running riot, or because tumors “learn” how to specifically trigger TReg-like responses, TRegs are common features of tumors.
Eliminating TRegs, in mouse models of cancer, often allows a strong immune response to the tumor. An interesting spin on this was shown in a recent J Immunol paper.1 It seems that the TRegs don’t generally suppress all the response, they shut down the responses to some targets harder than others:
Our results indicate, therefore, that depletion of Tregs uncovers cryptic responses to Ags that are shared among different tumor cell lines. CT26-specific T cell responses can be elicited by different forms of vaccination in the presence of regulatory cells, but in these cases T cell responses are highly focused on a single tumor-specific epitope …Taken together, these data suggest that immune responses to some Ags are more tightly regulated than others. 1
In other words, even though you might be able to force a protective immune response to a tumor by vaccinating in the presence of TRegs, when you get rid of TRegs the response is broader, and targets T cell epitopes that otherwise wouldn’t look like they’re epitopes at all.
I wonder if this goes on with “normal” (say, viral or other non-tumor) epitopes – whether this sort of thing might help explain some forms of immunodominance. I kind of doubt it, but the phenomenon does sounds a little like revealing a subdominant response.
I wonder also how this ties in with a recent paper that suggested TRegs in tumors are highly focused on a small subset of tumor epitopes. Could they be more broadly-based, but on epitopes that are otherwise invisible? Again, I kind of doubt it, but it’s an intriguing idea. Maybe the universe of tumor epitopes available for attack is much larger than we realize.
- James, E., Yeh, A., King, C., Korangy, F., Bailey, I., Boulanger, D., Van den Eynde, B., Murray, N., & Elliott, T. (2010). Differential Suppression of Tumor-Specific CD8+ T Cells by Regulatory T Cells The Journal of Immunology, 185 (9), 5048-5055 DOI: 10.4049/jimmunol.1000134[↩][↩]
[...] Go to Publisher to continue reading No Comments Biological sciences [...]
This is a very interesting post. I’m not going to pretend that I know a ton about TRegs, but the fact that one more thing can be made more harmful by finding a vaccine is discouraging. It’s very annoying that by trying to help something, we are only making it worse, or causing other problems. Such as with radiation of cancercous cells and tumors.
Interesting to be sure, but is the result then that the targeting of the T cell epitopes allows the tumor to again start producing TRegs without opposition, due to the fact that the vaccination has eliminated/depleted the T cell epitope count?
I was just reading an article that talked about the effect of diet on TReg’s, vegetarian/vegan vs carnivore, etc. I’ll look for it an post back.
Ian, nice post. I hope all is well in ATL.
I always wonder if tumor infiltrating T cells are effectors turned into Tregs by the tumor. I’ve seen several papers (one by the Belkaid group – gut immuno) that show Tregs (or at least CD4+CD25+Foxp3+) turning into IFNg secretors. I am sure the other way around (turn CD4+Tbet+ into Treg) should be possible, too… T cells seem to be more plastic than initially thought. So the learning (/growth advantage) by a tumor to instruct T cells to become a certain flavor seems very plausible for me. Also, why not instruct some Th17 to ramp up the angiogenesis when the nutrition/blood supply runs out?
Was it you that posted a discussion about inducing neoantigens in tumors by stabilizing and inducing transcription of introns (or non-coding RNAs) in tumor cells? I think its an interesting idea… I cant find the article – maybe it was a dream?