Nagaraj et al, nitrotyrosinated T cellsHaving beaten the theme of viral immune evasion into the ground, I’ll just change my aim a tiny bit and keep right on clubbing immune evasion. Cancers, like viruses, are (probably) controlled by the immune system,1 and, also like viruses, cancers evade cytotoxic T lymphocytes (CTL) in various ways.

Cancers are not viruses, however,2 and they don’t evade CTL in the same ways. One difference is that cancers evolve from square one each time. When you’re infected by a virus, that virus is the end-product of an unbroken chain of evolution that goes back millions or billions of years;3 it’s had time to evolve its own specialized molecules, which may or may not have been based on the host genome at some time but is now generally a standalone, distinct gene. Cancers don’t have that history. Each individual cancer arose independently within you,4 and it only has your lifespan5 in which to experiment with immune evasion.

Accordingly, what cancers tend to do is evade immunity by destruction rather than creation. Viruses are creative in their evasion techniques, crafting solid, workmanlike wooden shoes to cast into the gears of the immune system, while cancers blindly bludgeon their genomes until they break something the immune system needs. Most cancers (especially solid tumours), for example, contain genomic deletions that eliminate MHC class I alleles,6 and MHC class I alterations are associated with poor clinical outcomes.7

A part of this selective destruction can lead to cancer immune escape. I’ve talked about the way chronic viruses (like hepatitis C and HIV) alter their protein sequences in such a way as to mutate MHC class I epitopes, so that immunodominant CTL no longer recognize infected cells. Cancers are much like chronic infections and they too mutate immunodominant epitopes, so that CTL can no longer recognize them.8 This is, obviously, a real concern in cancer immunotherapy trials.

However, there are clearly lots of other ways that tumours avoid immune clearance that don’t involve mutation of their MHC class I system. In particular, CTL in the presence of tumours are often fairly ineffective; their targets may be present and the cells may be nominally susceptible, but the cells are simply not capable of dealing with the tumour. Again there are many reasons for this phenomenon. A new one was recently published in Nature Medicine:
Altered recognition of antigen is a mechanism of CD8(+) T cell tolerance in cancer.
Nagaraj, S., Gupta, K., Pisarev, V., Kinarsky, L., Sherman, S., Kang, L., et al. (2007).
Nat Med, 13(7), 828-835.

Tyrosines on TcRThis shows that tumours can also avoid CTL recognition by targeting the other side of the equation, the T cell receptor. (The TcR on a CTL recognizes MHC class I, and yes, editors always get exercised about using too much jargon and contractions.) The authors started with the previous finding that one cause of T cell tolerance of tumours is a suppressor cell, that infiltrates into the tumours and turns off — tolerizes — CTL that could otherwise attack the tumour. They show that, via release of peroxynitrite, these suppressor cells can physically alter the T cell receptor of the CTL, nitrating some of the tyrosines on the TcR (and also on the co-receptor, CD8); as a result, the TcR couldn’t bind to its target MHC class I. (The figure to the right shows the predicted location of the nitrated tyrosines on the TcR. At the top of this post: a stain for nitrotyrosines lights up T cells in a lymph node from a cancer patient — lymph nodes from normal individuals showed few if any nitrotyrosine-containing T cells. Both figures are from the supplementary info for the paper.)

Tumour resistance To test their hypothesis, Nagaraj et al. treated mice with uric acid (which, they say, specifically neutralizes peroxynitrite) at the same time as they transferred specific CTL into tumor-bearing mice. Transferring the CTL alone didn’t do much: they were tolerized, and the tumours weren’t affected. Treating with uric acid alone also did nothing.9 The combination of uric acid — to reduce peroxynitrite-triggered nitrotyrosine formation — with adoptive transfer of specific T cells, though, led to a significant reduction of tumor growth (but not to complete of the tumour). (Figure on the left shows tumour size after the various treatments — the “Vaccine + UA [Uric acid]” trace is the open circles. The tumours in those mice are less than 1/3 the size of the mice that just got CTL.)

Uric acid treatment is unlikely to be very practical for cancer patients, but if this work holds up, it may offer a way to enhance tumour immunogenicity, perhaps with some more specific targeting of the suppressor cells or some more specific way of reversing the tyrosine nitration. In any case, it suggests new ways that tumours (and perhaps pathogens) could block T cell recognition.


  1. The whole question of whether cancers really are controlled by the immune system is still somewhat controversial, but the weight of the evidence is that they are. The back-and-forth on this issue is probably worth a blogpost some time, if only because it will help me get the story straight in my own mind.[]
  2. Even the cancers that are caused by viruses aren’t viruses[]
  3. Depending on which origin of viruses you’re considering[]
  4. Aside from a few weird and whacky things like transmissible canine venereal tumours and the Tasmanian Devil transmissible tumours.[]
  5. What’s left of it … []
  6. A lot of references cite relatively low numbers for this phenomenon, like “15% – 60% of solid tumours”. Until quite recently, screening of tumors for loss of MHC class I was relatively perfunctory and coarse, and probably missed many of the smaller and more focused deletions, so I think the higher end of the ranges is probably much more accurate, or may even still be an underestimate. Work by Soldano Ferrone, where he has looked very carefully at a relatively small set of tumours, turned up MHC class I/antigen presentation defects in virtually every one, and many of those would have been missed by standard approaches. A review is: Chang, C. C. & Ferrone, S. (2007). Immune selective pressure and HLA class I antigen defects in malignant lesions. Cancer Immunol Immunother, 56(2), 227-236.[]
  7. Bangia, N. & Ferrone, S. (2006). Antigen presentation machinery (APM) modulation and soluble HLA molecules in the tumor microenvironment: do they provide tumor cells with escape mechanisms from recognition by cytotoxic T lymphocytes? Immunol Invest, 35(3-4), 485-503. []
  8. Singh, R. & Paterson, Y. (2007). Immunoediting sculpts tumor epitopes during immunotherapy. Cancer Res, 67(5), 1887-1892.[]
  9. Uric acid is a potent immune stimulant, but only in the crystal form. The authors treated the mice with soluble uric acid and argue this avoids this potential confounder. However, as I recall, uric acid in the body is very close to the crystallization point normally, and adding in more, even soluble, uric acid might kick it over the edge into crystallizing; so this is still a potential artifact in this study. But that might be less of a concern with intraperitoneal injections.[]