Melanoma antigens
Melanoma antigens

The other day I talked about about resurrecting the antiviral response in HIV patients. 1 Antiviral T cells in HIV (and other chronic immune responses) become exhausted: After long exposure to antigen, the cytotoxic T lymphocytes (CTL) become dysfunctional, incapable of mounting a potent response to the virus. This exhausted state is correlated with a number of surface flags, especially the molecules PD-1 and CTLA-4. These aren’t merely flags, but rather they actually transmit the signal to become exhausted.  So it turns out that blocking PD-1 reversed the exhaustion, restored  CTL to their youthful vigor, and allowed them to effectively suppress the virus replication. All the monkeys treated with PD-1 blockade survived, whereas most of those left untreated died within a few months.

As I say, exhaustion isn’t unique to HIV. Probably any chronic exposure to antigen tends to cause  T cell inhibition. There’s molecular logic behind this; if you’ve been fighting an infection for many months, you’re probably not winning, and your immune response is probably doing as much damage as the infection would. Or — even worse — you’re not fighting an infection at all, you’re attacking yourself (because of course you can’t eliminate your own antigens). So maybe it’s time to back off a few notches on the attack and try to reach an accommodation with the antigen.

There are a number of cases — probably many cases — where this seems to work well. Rodents that are chronically infected with hantaviruses turn on a regulatory T cell (TReg) type response, shutting own the attack on the virus and letting them become persistent infections. This comes with some cost, but not too much; probably the infected rodents do much better by letting the virus persist, than if they kept trying to fight the infection.

TRegs
TRegs in skin

There’s another condition when T cells chronically attempt to attack foreign antigen, frequently fail to eliminate it, and become inhibited. This is, of course, cancer. The nature of the CTL inhibition may not be exactly the same as in HIV infections and other CTL exhaustion scenarios, but it’s pretty clear that in general, CTL are not very effective against tumors. After all, most tumors don’t spontaneously regress after a few weeks.

This is probably because when CTL are effective against tumors, that tumor never becomes detectable. In other words, we are only aware of those cancer where CTL are ineffective. (See here (part I) and here (part II) for more detail.) What often happens with tumors, that may be less of an issue with virus infections, is that TRegs become activated and move into the tumor; TRegs shut down aggressive immune responses. As a result, even if you infuse the patient with active anti-tumor cells, or vaccinate and activate the anti-tumor response that way, the anti-tumor response is often quickly shut down by the TRegs and the response never really goes very far.

So can the ineffective T cell response in tumors be reversed, as was done with the ineffective T cell response in SIV? It certainly can — but, as with most anti-tumor immune therapies, it doesn’t work all the time.

With tumors, unlike virus-associated exhaustion, the CTL dysfunction seems to be often associated with the CTLA-4 cell marker. As with PD-1, CTLA-4 isn’t just a marker, it transmits signals into the T cell and actively drives the cells into an inhibited state. (CTLA-4 is probably part of the TReg arsenal, though not the whole of it.) So blocking CTLA-4 in tumor patients has been of intense interest for quite a long time — I think Jim Allison first tried it well over a decade ago2. In general the results have been encouraging, but unspectacular. (It seems that immune treatment of cancer is always encouraging but unspectacular. The problem has been to get consistent effectiveness, rather than occasional amazing cures.)

Melanoma blood vessel
Melanoma blood vessel

This isn’t a safe and innocuous treatment. CTLA-4 is part of the normal immune regulation machinery, and given that, it’s not surprising that CTLA-4 blockade often leads to autoimmunity. In fact, it seems that the more effective the anti-tumor effect is, the more likely the patient is to develop autoimmunity – sometimes quite severe. Compare this to the PD-1 blockade in monkeys, where there wasn’t much autoimmunity, if any.  (Incidentally, before the PD-1 blockade that seemed to work, CTLA-4 blockade has been tried in SIV-infected monkeys.  It didn’t seem to do much.)

A recent paper3 has connected CTLA-4 blockade to the emerging theme of polyfunctionality. As I’ve noted before, it’s become clear over the past couple of years that not all CTL are equal. In HIV infection, polyfunctional CTL — CTL that are capable of producing a wide range of effects, rather than just one or two — are often linked to suppression of the virus. In melanoma patients treated with CTLA-4 blockade, not only were more T cells specific for melanoma antigens present, but those CTL were more likely to be polyfunctional — thus more likely to be effective at destroying the tumor — and those patients were much more likely to have regression of their tumors than in people without CTLA-4 blockade.

So the concept that TRegs — or some other inhibitory effect associated with CTLA-4 — suppress anti-tumor immune responses is likely to be correct, and it seems that at least in some cases it’s possible to override that inhibition and drive T cells to once again attack the tumor effectively. When that happens, cancer can be cured. It’s just a question of being able to do this on a consistent basis. Unfortunately, that’s still the hard part.


  1. The actual experiment was done in SIV infected macaques, but of course the hope is that it will translate to the human virus as well.
    []
  2. Enhancement of antitumor immunity by CTLA-4 blockade. Leach DR, Krummel MF, Allison JP. Science. 1996 Mar 22;271(5256):1734-6.
    []
  3. Yuan, J., Gnjatic, S., Li, H., Powel, S., Gallardo, H., Ritter, E., Ku, G., Jungbluth, A., Segal, N., Rasalan, T., Manukian, G., Xu, Y., Roman, R., Terzulli, S., Heywood, M., Pogoriler, E., Ritter, G., Old, L., Allison, J., & Wolchok, J. (2008). CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit Proceedings of the National Academy of Sciences, 105 (51), 20410-20415 DOI: 10.1073/pnas.0810114105
    []