Breast cancer cellsIt’s pretty much an article of faith for me, as an immunologist, that our immune system normally protects us against cancer. The question is, then, why do we see so much cancer? And why, when we see them, does the immune system pretty much leave them alone, instead of, you know, protecting us?

This is actually a long-running controversy that has gone back and forth over the years. There’s too much history to treat all in one post,1 and indeed there’s circumstantial evidence arguing that in fact immune systems are not major players in cancer resistance. For example, immune deficient mice and humans don’t have huge increases in the frequency of common cancers (though they do, often, develop cancers that are otherwise rare). However, the pendulum swing at the moment has it that the immune system does represent a major barrier to cancer progression.

Our current understanding of tumor development is that it’s a multi-step process. 2 A normal cell undergoes sequential changes in its genome and epigenome that eventually turns it into a pre-cancerous cell, then an overtly cancerous cell, and finally into a malignant cell. Each step in the process represents a checkpoint that blocks progression of most of the cells that reach it. Checkpoints include things like cell-cycle deregulation, independence from growth factors, and so on. As each step is overcome, the new clone of proto-cancerous cells proliferates and expands until it reaches the next checkpoint. At that point, almost all the clones are stopped from progressing further, but if a fortuitous mutation is present in one of the individual cells, it escapes that selection event, proliferates and expands, and moves on to the next point.

Galone Fig 3
Cancer survival and appropriate immune response

The present model is that the immune system is just one checkpoint (though probably a fairly significant barrier) that the developing cancer cell must overcome. That means that by the time we can detect a cancer, it’s already been selected to be immune resistant. The cancers that were susceptible to the immune system were killed off when they were just a little cluster of cells, long before there was anything we could identify. The surprising thing, then, is not that the immune system doesn’t eliminate cancers; it’s that the immune system sometimes actually does contribute to cancer survival. Tumors escape from immune recognition in several ways, and the immune escape is not necessarily irreversible.

Blogging on Peer-Reviewed ResearchFor example, I’ve previously mentioned the recent suggestion that it’s actually the immune system that mediates tumor clearance after chemotherapy, and that the main role of the chemotherapeutic agent is to make the cancer cells recognizable to the immune cells. In other cases, tumor vaccines3 or artificially enhanced T cells4 have been able to break through the tumor’s cloak of invisibility.

Even more encouragingly, it seems that immune responses may actually be ongoing even within a tumor, though perhaps at a level that’s inadequate to keep up with the tumor, and this immune response may be enough to prevent recurrence after surgery. In fact, it was shown last year that spontaneous, appropriate anti-tumor immune responses in colo-rectal tumors correlate well with a good clinical response:5

Our results suggest that once human CRCs6 become clinically detectable, the adaptive immune response plays a role in preventing tumor recurrence. … We found a positive correlation between the presence of markers for TH1 polarization and of cytotoxic and memory T cells and a low incidence of tumor recurrence. This argues for immune-mediated rejection of persistent tumor cells after surgery. We hypothesize that the trafficking properties and long-lasting anti-tumor capacity of memory T cells play a central role in the control of tumor recurrence. … This suggests that time to recurrence and overall survival time are governed in large part by the state of the local adaptive immune response.


  1. Note the cunning way I escape having to work out the details of the history[]
  2. For example, Land, H., Parada, L. F., and Weinberg, R. A. (1983). Cellular oncogenes and multistep carcinogenesis. Science 222, 771-778. []
  3. E.g. Slingluff, C. L. J., Petroni, G. R., Chianese-Bullock, K. A., Smolkin, M. E., Hibbitts, S., Murphy, C., Johansen, N., Grosh, W. W., Yamshchikov, G. V., Neese, P. Y., Patterson, J. W., Fink, R., and Rehm, P. K. (2007). Immunologic and Clinical Outcomes of a Randomized Phase II Trial of Two Multipeptide Vaccines for Melanoma in the Adjuvant Setting. Clin Cancer Res 13, 6386-6395. []
  4. Morgan, R. A., Dudley, M. E., Wunderlich, J. R., Hughes, M. S., Yang, J. C., Sherry, R. M., Royal, R. E., Topalian, S. L., Kammula, U. S., Restifo, N. P., Zheng, Z., Nahvi, A., de Vries, C. R., Rogers-Freezer, L. J., Mavroukakis, S. A., and Rosenberg, S. A. (2006). Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314, 126-129. []
  5. Galon, J., Costes, A., Sanchez-Cabo, F., Kirilovsky, A., Mlecnik, B., Lagorce-Pages, C., Tosolini, M., Camus, M., Berger, A., Wind, P., Zinzindohoue, F., Bruneval, P., Cugnenc, P. H., Trajanoski, Z., Fridman, W. H., and Pages, F. (2006). Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960-1964. []
  6. Colo-Rectal Cancers[]