Metchnikov - Lecons sur la pathologie
Metchnikov: “Lecons sur la pathologie” (1892)

There are times when you just feel like the universe is out to get you. For example, we know that inflammation can drive tumor formation; but a paper just came out that suggests reducing inflammation can also drive tumor formation. 1 It doesn’t seem fair.

I’ve previously mentioned the link between inflammation and tumorigenesis, which is probably at least partly because the inflammation produces reactive oxygen and nitrogen species (RONS ) that are tumorigenic.

I’ve also talked about the link between reduced inflammation and ongoing tumors (for example, here, here, and here). What seems to be going on here is that regulatory T cells (TRegs) are induced by tumors, and these TRegs shut down anti-tumor immunity.

So far, these findings aren’t really contradictory. Increasing inflammation before a tumor is present makes tumors more likely to form. After the tumor has formed, reducing inflammation makes the tumor more likely to persist. The universe-is-against-us part comes from the suggestion that reducing inflammation (via TRegs) before tumor formation, also makes the tumors more likely to form.

This may be a special case. The paper from Philip Dennis’s group 1 looked at a specific set of cancers, those associated with K-Ras mutations (linked to smoking-induced lung cancer). K-Ras activation itself triggers inflammation (for reasons I, at any rate, don’t understand). When K-Ras is activated, as well as inflammation, TRegs move into the area, and presumably reduce the inflammation. Depleting the TRegs (and therefore increasing the inflammation) decreased the number of tumors by 75% — the opposite of what you’d expect if inflammatory RONS were driving tumorigenesis.

Smoking / cancer

A common feature linking smoking induced K-Ras mutations in human lung cancer and preclinical models driven by tobacco carcinogens that cause K-Ras mutations is inflammation. In both cases, the presence of Foxp3+ cells is likely important for limiting the extent of inflammation and tissue damage, albeit at a potential cost of promoting tumorigenesis. 1

In later-stage tumors the situation became more consistent with other work — getting rid of TRegs reduced the tumors, suggesting that these tumors were depending on TRegs to prevent immune clearance:

Aggressive and invasive K-Ras-induced adenocarcinomas (IO33 and K-RasLA2) remained sensitive to more direct targeting of Foxp3+ cells through a neutralizing anti-CD25 antibody or genetic deletion. This indicates that direct Treg cell depletion strategies that are being evaluated clinically could have therapeutic value in more advanced stages of K-Ras driven lung cancer. 1

My question here is whether the early inflammation is kind of a red herring. Could the TReg depletion in the early stages be reducing the anti-tumor immune response in a specific way, just as in the later stages of tumor formation? That is, could the TReg depletion lead to a tumor-specific immune response, which prevents tumors from forming? In this case the inflammation could still be driving the tumor formation, but the increase in tumor formation would be outweighed by the simultaneous increase in anti-tumor immunity. I don’t know quite how to test this, but perhaps doing the same experiment in mice lacking, say, CD8 T cells might be interesting. (Such mice should still have the early inflammation and the TRegs, but may have a less effective immune response. It’s not a perfect experiment, though, for reasons that are probably too complex to go into here.)

  1. Granville, C., Memmott, R., Balogh, A., Mariotti, J., Kawabata, S., Han, W., LoPiccolo, J., Foley, J., Liewehr, D., Steinberg, S., Fowler, D., Hollander, M., & Dennis, P. (2009). A Central Role for Foxp3+ Regulatory T Cells in K-Ras-Driven Lung Tumorigenesis PLoS ONE, 4 (3) DOI: 10.1371/journal.pone.0005061[][][][]