Comments on: Brainwashed killers

By: Peer

Peer — Mon, 26 Oct 2009 15:56:36 +0000

The effects of chemotherapeutic agents are very interesting indeed. I think that the antiproliferatives are generally immunosuppresive but the idea of hypoxic anti-tumor immune response modulation is intriguing. Hypoxia and inflammation is a very complex mixture in my opinion and just browsing the literature I started to realize how little I know.

While searching, I found it very intriguing that 1. adenosine receptor activation by adenosine produced in hypoxia matures DCs, but at the same time reduces T cell effector responses directly, 2. Contrarily to Teffs, Tregs are activated by adenosine receptor ligation, which in turn produce more adenosine 3. There is a shift towards a Th2 (if you believe in the Th1/Th2 paradigm) response.

Apparently Michail V. Sitkovsky has found his niche in T cells and hypoxia.

I am sure there is more going on than we presently know.

By: iayork

iayork — Fri, 23 Oct 2009 14:23:32 +0000

Yes, one of the major hypotheses for tumor-induced tolerance is effects on DC — not just failure to receive maturation signals, but also active signals (like TGFbeta, and many others) that probably drive the DC into a tolerogenic state. That said, there can also be plenty of potential activators in a tumor environment, mainly through cell death (e.g. through low oxygenation if there’s not enough angiogenesis, and general increased apoptotic cells death etc); so it’s not inevitable that DC will follow the tolerogenic route.

The effect of chemotherapy on immune responsiveness, that I’ve talked about here a couple of times, is proposed to be via increased immunogenicity by increasing cell death — a difference in degree rather than kind, I think.

By: peer

peer — Thu, 22 Oct 2009 23:10:19 +0000

Ian, I think tumor immunology is also interesting from the dendritic cell perspective. How does a dc receive maturation signals to present tumor antigens optimally to elicit an effector cell population? Or does it not? So that the tolerance induction is a result of the lack of dc maturation signals while presenting tumor antigens.

By: iayork

iayork — Thu, 22 Oct 2009 20:37:13 +0000

Interesting question. I think the mechanism of immunosuppression is a natural one, for the reason you say — avoiding a chronic immune response. Whether it’s “supposed” to happen this way for tumors, or whether the tumors are happening to take advantage of a natural mechanism, is a much harder question (and probably is too teleological to answer very well). I think most likely it’s the latter, though — the tumors are taking advantage of it, it’s not in the body’s best interest to let the tumors go. Hard or impossible to prove, though.

By: hat_eater

hat_eater — Thu, 22 Oct 2009 12:21:44 +0000

A question from a layman – is it possible that this immunosuppression mechanism is an adaptation? With notable exceptions like pancreatic cancer, one can live for years with a tumor, while a powerful and prolonged immune response could kill our protohuman ancestors in weeks, not directly, but by starting a vicious cycle of weakness and starvation.