|TRegs infiltrate into a tumor|
One of the reasons the immune system doesn’t destroy tumors is the presence of regulatory T cells (TRegs) that actively shut down the anti-tumor response. For once, there’s a little bit of encouraging news on that front.
TRegs are normal parts of the immune system. They actively prevent other T cells (and so on) from attacking their target. 1 What’s more, TRegs are antigen-specific. That is, they recognize a specific target, just as do other T cells, but instead of responding by, say, destroying the cells (like cytotoxic T lymphocyte) or by releasing interferon (like a T helper cell) a TReg’s response to antigen is to prevent other T cells from doing anything in response to that antigen. In other words, TRegs cause an antigen-specific inhibition of the conventional immune response. 2
Back to tumors. We know that immune responses don’t routinely eliminate tumors by the time they’re detectable. There is some evidence that lots of very small, proto-tumors, are in fact destroyed by the immune system very early on, before they’re clinically detectable, but those tumors that survive that attack seem to be pretty resistant to immune control. At least part of that resistance is because TRegs get co-opted into the tumor’s control (see here, and references therein, for more on that).
So if TRegs are antigen-specific, and TRegs control immune responses to the tumor, what are the tumor antigens that are driving the TRegs?
I would have assumed that TRegs are looking at many, many tumor antigens, including both normal self antigens3 as well as classical tumor antigens.4 But a recent paper5 suggests, to my surprise, that this assumption is wrong. Instead, “Tregs in tumor patients were highly specific for a distinct set of only a few tumor antigens“. 5 What’s more, eliminating TRegs cranked up the functional immune response, but only to those antigens TRegs recognized — as you’d expect, if the suppression is indeed antigen specific.
This is interesting for several reasons. If TRegs can be specific for tumor antigens, then at least in theory ((In practice, we don’t quite have the tools yet, I think) it should be possible to turn off these TRegs while leaving the bulk of TRegs intact (and therefore not precipitating violent autoimmunity). It also suggests that if the TRegs are only suppressing a subset of effector T cells, there’s something else preventing most effector T cells from, well, effecting. Maybe those are antigen non-specific TRegs, or maybe there’s something else we need to know about.
I’d like to see this sort of study replicated, and a little more fine-tuning on identifying the TReg’s targets (the readout was intentionally fairly coarse here, in order to identify as many as possible). Still, it’s an unexpected, and potentially very useful, observation.
- It’s still not quite clear how they do this[↩]
- There are also antigen-nonspecific TRegs, but we will ignore them for now. They’re not as effective as the antigen-specific sort, anyway.[↩]
- Because TRegs, unlike most immune cells, can be stimulated by normal self antigens[↩]
- That is, antigens that are mutated, or dysregulated, and that therefore act as standard targets for immune cells[↩]
- Bonertz, A., Weitz, J., Pietsch, D., Rahbari, N., Schlude, C., Ge, Y., Juenger, S., Vlodavsky, I., Khazaie, K., Jaeger, D., Reissfelder, C., Antolovic, D., Aigner, M., Koch, M., & Beckhove, P. (2009). Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma Journal of Clinical Investigation DOI: 10.1172/JCI39608[↩][↩]