No one is safe from cancer (ACS)We know a bunch of ways by which tumors avoid the immune system. Lots of tumors are defective in antigen presentation and natural killer cell recognition (that is, they should be poorly recognized by cytotoxic lymphocytes). These probably usually arise quite early in tumor development, before the tumor becomes detectable. By the time tumors are clinically apparent, there are often lots of regulatory T cells (TRegs, the cells that normally suppress immune responses that are directed against “self”) directed to the tumor, and those TRegs prevent anti-tumor immune responses from developing (see here for more on that).

If you’re trying to trigger an immune response to the tumor, you probably need to overcome both the defective T cell recognition of individual cells, and (especially) the suppressive TReg response that the whole tumor has induced. A new paper1 points out yet another problem that may need to be overcome before immunotherapy of tumors becomes generally useful.

One phenomenon that’s often associated with a better prognosis for tumors is the presence of T cells infiltrating the tumor (for example, see here and here). Presumably these infiltrating T cells are part of an immune attack on the tumor, and that’s causing the better prognosis (though it’s also possible that, say, the tumor is dying more rapidly for other reasons and that’s attracting T cells, but let’s not get distracted here). If so, cranking up the number of anti-tumor T cells and cranking up their activity by reducing the number of TRegs, should increase the number of infiltrating T cells and improve the prognosis. Jim Allison’s and Dan Littman’s groups show that’s not necessarily true.1

Tumor-infiltrating T cells and adhesion factors
Boosting adhesion molecule expression in tumor blood vessels
(red) allows more tumor-killing T cells (green) to gain access

A puzzling finding has been that getting rid of TRegs apparently does crank up the number of activity of circulating anti-tumor T cells, but does not have much clinical effect on the actual tumors. “Our data indicate that depletion of T reg cells after tumor establishment results in a dissociation between systemic immunity and objective clinical responses.1 Quezada et al. suggest that this is at least partly because even after getting rid of TRegs, T cells still have trouble getting in to tumors (that is, they remain circulating T cells, and don’t become infiltrating T cells), and this may be because the tumor blood supply is abnormal.

Several studies suggest that tumor vasculature may differ from regular vasculature upon tumor establishment, and that this altered vasculature is less permeable to tumor-reactive lymphocytes.1

The good news is that this may be a manageable problem, at least in some tumors; because radiation therapy seems to restore the tumor blood vessels to a more normal state, allowing better infiltration of anti-tumor T cells. ( If you’re expanding the number of anti-tumor T cells artificially, irradiation also helps the expanded T cells “take” in the patient, and may have other immunological benefits as well.) When Quezada et al. incorporated radiation into a rather complex series of immunostimulatory steps,  mice succeeded in rejecting established tumors.

Whether there is any clinical relevance to humans here still isn’t proven, but as far as I can see, all of the components of the treatment they used here have been used as anti-tumor therapy in humans — so it may be worth merging them and seeing if the end result is as encouraging as in mice.

  1. S. A. Quezada, K. S. Peggs, T. R. Simpson, Y. Shen, D. R. Littman, J. P. Allison (2008). Limited tumor infiltration by activated T effector cells restricts the therapeutic activity of regulatory T cell depletion against established melanoma Journal of Experimental Medicine, 205 (9), 2125-2138 DOI: 10.1084/jem.20080099[][][][]