Clark & Kupper: Blood, 1 January 2007, Vol. 109, No. 1, pp. 194-202. A while ago, talking about tumor development, I said that “tumors normally develop ways to avoid immunity.” It’s that ability to evade the immune system that allows tumors to escape from the equilibrium phase, when they’re a mere harmless handful of cells held in check by the immune system, and become outright clinically-detectable tumors.

How do tumors avoid immunity?

There are many ways. Remember that tumors are not like viruses; each tumor arises de novo and has only its host’s lifespan in which to evolve. It has no connection to other tumors of the same kind; there is no evolutionary linkage. All human cytomegaloviruses have a common ancestor, but no two colon cancers have the same ancestor. 1 That means that each tumor must find its own solution to every problem rather than relying on its ancestors’ solutions. (And if most colon carcinomas, say, adopt the same solution, we have to look at what factors make that solution particularly accessible to, or appropriate for, that particular type of cancer.)

That said, there are some mechanisms that are very widely used by tumors to evade the immune system, and regulatory T cells (TRegs) are one of them. That’s probably at least in part because TRegs’ natural functions include suppressing immune responses to self antigens and reducing inflammation in chronic exposure to antigen. It’s relatively easy to get the TRegs to do their job a little more enthusiastically.

TReg (J Clin Invest cover)(TRegs are T cells that specifically down-regulate immune responses; without TRegs, immune responses explode and cause massive damage. People without TRegs have terrible, usually fatal, autoimmune and inflammatory disease, so you don’t want to just blithely eliminate them to get a “better” immune response. )

It was suggested nearly 30 years ago that TRegs contributed to tumor growth,2 but the whole I-J fiasco set the field back a long way, and it wasn’t until relatively recently that the questions were revisited. 3 It’s now pretty clear that, in fact, TRegs are often abundant in tumors, and actively shut down immune responses to the tumors. For example, it’s been shown recently that tumors with relatively more TRegs have a worse prognosis:4

In patients with undesirable outcome, the balance is tipped in favor of Tregs (high Tregs and low activated CTLs), whereas in patients with relatively desirable outcome, the balance is tipped toward effector T cells (low Tregs and high activated CTLs).

Eliminating TRegs from mice with experimental tumors caused rejection of the tumors,5 so as you’d expect, there’s a lot of interest in this sort of approach to cancer therapy.

Relevant previous posts
• … and immune escape
• … and TLRs
• … and immunity
• … the Three E’s of
• … and equilibrium
Regulatory T cells:
• … and the I-J story
• … and persistent viruses
A small step forward was described recently in PNAS. 6 “Classic” TRegs are antigen-specific; they recognize antigen just as do T Helper cells, but instead of responding by stimulating immune responses, the TRegs respond to their antigen by suppressing local responses. There are also non-antigen-specific cells that act something like TRegs (though not as effectively). This paper shows that patients with melanoma have circulating (not just tumor-infiltrating) TRegs that are specific for tumor antigens.


This is a nice little paper, but I don’t think it represents a very large or surprising advance.7 It’s already known that tumor-infiltrating TRegs can be tumor-antigen-specific;8 it’s known that patients with melanoma have increased numbers of circulating TRegs;9 and it’s also been shown that tumor-specific T cells are in circulation in patients with melanoma. 10 So this (as far as I can see) extends several prior observations, but in an unsurprising direction.

Also, unless I’m missing something (which wouldn’t be new), I don’t see just how knowing or identifying circulating TReg antigens will help with treatment or prognosis. One possibility that occurs to me is that these circulating TRegs may help protect metastases from rejection. If the TRegs were all infiltrating the tumor, then perhaps the immune system would be able to deal with the small number of metastatic cells that are spreading throughout lymphatics and so on, whereas if TRegs are also circulating then the metastatic cells might be protected. I’m not entirely sure about the actual relevance of this, because even if TRegs were only tumor-infiltrating I think there would be plenty of opportunity to tolerize tumor-specific T cells.

Still, it’s always important to understand the system.

Just as a final cautionary note: As I said up at the top, tumors are all different. Different classes of tumors may be particularly able to move along certain immune evasion pathways because of their underlying characteristics. For example, inflammatory infiltrate within some tumors is a good sign11 (presumably because it implies that there is an active immune response against the tumor), yet in other classes of tumor the same kind of infiltrate is a bad sign, perhaps because it indicates TReg infiltration and a suppressive environment. Even within classes of tumors there are inevitably variations. It may not be possible to develop universal rules for tumor immune treatment; but it may be possible to find some useful guidelines.

  1. With bizarre exceptions like transmissible canine veneral tumor and Tasmanian Devil tumor. []
  2. Berendt, M.J. & North, R.J., 1980. T-cell-mediated suppression of anti-tumor immunity. An explanation for progressive growth of an immunogenic tumor. The Journal of experimental medicine, 151(1), p.69-80.[]
  3. A nice review: Zou, W., 2006. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol, 6(4), p.295-307. []
  4. Gao, Q. et al., 2007. Intratumoral Balance of Regulatory and Cytotoxic T Cells Is Associated With Prognosis of Hepatocellular Carcinoma After Resection. J Clin Oncol, 25(18), p.2586-2593. DOI: 10.1200/JCO.2006.09.4565 []
  5. Shimizu, J., Yamazaki, S., & Sakaguchi, S., 1999. Induction of Tumor Immunity by Removing CD25+CD4+ T Cells: A Common Basis Between Tumor Immunity and Autoimmunity. J Immunol, 163(10), p.5211-5218.
    Viehl, C. T., Moore, T. T., Liyanage, U. K., Frey, D. M., Ehlers, J. P., Eberlein, T. J., Goedegebuure, P. S., and Linehan, D. C. (2006). Depletion of CD4+CD25+ regulatory T cells promotes a tumor-specific immune response in pancreas cancer-bearing mice. Ann Surg Oncol 13, 1252-1258.[]
  6. Vence, L. et al., 2007. Circulating tumor antigen-specific regulatory T cells in patients with metastatic melanoma. Proceedings of the National Academy of Sciences, 104(52), p.20884-20889. []
  7. I mention it here mainly because it reminded me that this is a subject I wanted to talk about.[]
  8. see Wang, R., 2006. Functional control of regulatory T cells and cancer immunotherapy. Seminars in Cancer Biology, 16(2), p.106-114. for a review[]
  9. McCarter, M.D. et al., 2007. Immunosuppressive dendritic and regulatory T cells are upregulated in melanoma patients. Annals of surgical oncology, 14(10), p.2854-60.[]
  10. For example, Michalek, J. et al., 2007. Detection and Long-Term In Vivo Monitoring of Individual Tumor-Specific T Cell Clones in Patients with Metastatic Melanoma. J Immunol, 178(11), p.6789-6795.

    and Bioley, G. et al., 2006. Melan-A/MART-1-specific CD4 T cells in melanoma patients: identification of new epitopes and ex vivo visualization of specific T cells by MHC class II tetramers. Journal of immunology 177(10), p.6769-79.[]

  11. For example, Eerola AK, Soini Y, Paakko P. A high number of tumor-infiltrating lymphocytes are associated with a small tumor size, low tumor stage, and a favorable prognosis in operated small cell lung carcinoma. Clin Cancer Res. 2000; 6: 1875-1881[]