How exactly does the immune system fight cancer? And what does that imply for immunotherapy opportunities?
In 1909, Paul Ehrlich proposed the hypothesis that the body protects itself from cancer via immune mechanisms. Fifty years later, Lewis Thomas and F. Macfarlane Burnet revisited the hypothesis. Thomas’ argument was evolutionary — he said that complex organisms must develop mechanisms to protect against neoplastic disease as they develop mechanisms mediating homograft rejection. By contrast, Burnet’s argument was functional; he believed tumor-specific antigens could provoke an immune response. In 1964 the first tumor-specific antigens were observed in mice.
However, it wasn’t until the 1990s that the immune surveillance hypothesis (that the immune system fights cancer) was widely accepted. This is because nude mice (mice without thymuses, which have greatly reduced numbers of T cells) don’t have higher rates of cancer than normal mice, either spontaneous or induced by carcinogens. If immune-deficient mice aren’t getting more cancer, went the theory, then the immune system can’t be targeting tumors. What wasn’t known at the time was that nude mice do have some T-cells, a working innate immune system, and natural killer (NK) cells, which weren’t discovered until 1975. What really confirmed the immune surveillance hypothesis were other kinds of immunodeficient mice which do have elevated rates of cancer.
The cytokine IFN-gamma has been shown to protect the host against spontaneous, chemically-induced, and transplanted tumors. Mice lacking the IFN-gamma receptor were 10-20x as sensitive to tumor induction. (STAT1, the famous oncogene, is the transcription factor that mediates most of IFN-gamma’s effects on cells. Mice with mutations in STAT1 are unable to resist injected tumors.) IFN-gamma is a signaling molecule involved in both adaptive and innate immunity. It is the key cytokine that prompts T cells (CD4+) to develop into Th1 cells. It also promotes NK cell activity, NO synthesis, and much more.
NK cells were discovered in 1975 as a distinct cell type that could kill tumor cells w/o prior sensitization. NK cells are cytotoxic lymphocytes. They exocytose granules containing perforin, which kill cells by inducing apoptosis. Perforin, true to its name, punches holes in cell membranes; perforin-deficient mice are 2-3x as likely to produce tumors in response to carcinogens. Also, NK cell ligands binding to TNF receptor superfamily members on cancer cells induce cytotoxicity.
NK-deficient mice get more tumors. Infiltration of tumors with NK cells in humans is a positive prognostic indicator, and lower NK-like cytotoxicity of peripheral blood lymphocytes is predictive of cancer risk.
NKG2DL is an activating receptor on NK cells and some other cells. Its ligands do not occur on healthy tissue. NKG2DL expression is activated by stresses such as heat shock, viral infection, DNA damage, or UV radiation. NKG2DL ligands have been observed on lots of tumor types. Cancer cells “shed” these ligands a lot, though, which allows them to evade NK attacks.
MICA and MICB are examples of cellular-stress-related NKG2D ligands. Tumor cells expressing MICA/B are more vulnerable to NK cells. MICA/B are found in a high percentage of carcinomas; the only healthy tissue that contains these ligands is gastrointestinal epithelium.
In short, we are now aware of various lines of evidence that the immune system does indeed attack cancers, and that certain kinds of immune deficiency make individuals more susceptible to cancer. (The increased rates of cancers in immunosuppressed individuals such as AIDS patients and transplant recipients are further evidence for the immunosurveillance hypothesis.)
The current theory of the immune response to cancer goes as follows:
- As the tumor physically expands (causing pressure on surrounding tissues and growing new blood vessels) the innate immune system starts producing inflammation.
- NK cells and T cells are recruited to the tumor site.
- T cells and NK cells produce tons of IFN-gamma! This amplifies the immune response!
- IFN-gamma activates macrophages
- macrophages produce IL-2
- IL-2 stimulates NK cells to produce more IFN-gamma! GOTO 3 and repeat, in a positive feedback loop!
- IFN-gamma stimulates macrophages and NK cells to do more tumor killing
- IFN-gamma causes apoptosis and anti-growth processes in the tumor itself
- Now the adaptive immune response starts; dendritic cells are recruited to the tumor site
- dendritic cells show tumor antigens to T cells, which home to the tumor
- tumor-specific T cells kill tumor cells
- T cells produce even more IFN-gamma! GOTO 3, more positive feedback loop!
Clearly, IFN-gamma is a very big deal here. IFN-gamma is involved in the Th1 (or cellular) immune response, which trades off against the Th2 (humoral) immune response. There’s a simplistic but suggestive theory that a lot of the diseases of modern aging (heart disease, cancer, diabetes, Alzheimer’s) are associated with a shift in the balance of the immune system towards Th2 and away from Th1 responses; this may be relevant here.
Toll-like receptors, which are expressed on tumor cells and release IL-6, a Th2-promoting cytokine, tend to suppress the immune response to tumors, helping the tumor evade immune surveillance. Blocking the toll-like receptor slows tumor growth and prolongs survival in mice. This is also consistent with the Th1/Th2 balance hypothesis.
There is a whole zoo of tumor-specific antigens which are more common in tumor cells than in healthy cells and which the immune system can recognize. Some of these (gp100, NY-ESO-1, p53, HER2, etc) have been used as drug targets. The problem with this strategy is that, as tumors advance, they evade immune surveillance by losing these distinctive antigens, through a process of natural selection. It’s not uncommon to lose all HLA class I antigens in many carcinomas.
Spontaneous remissions of cancers often look immunological in origin, but they are rare. Normally, once a cancer is large enough to observe macroscopically, it only grows or stabilizes, never shrinks; if the immune system could reliably destroy macroscopic solid tumors, you’d see tumors shrinking and growing in size without treatment. The current theory is that “escape” from immune surveillance happens at a cellular level; cells that present antigens die, cells that don’t survive, and so the cancer shifts over time to become resistant to the immune system. This suggests that immunotherapies which target specific antigens face similar kinds of strategic considerations to antibiotics; you have to be careful to avoid promoting resistance. (One consequence of this hypothesis is that giving courses of immunotherapy that are too short in duration could be directly counterproductive.)
The immunology of cancer really is complex and I’ve really only scratched the surface here; what I’m trying to do is to generalize from the standard picture given in the research literature and come to some conclusions as to what types of treatment approaches are and are not likely to be fruitful. My suspicion is that antigen-specific immunotherapies, like growth factor-specific targeted therapies, are not particularly likely to work a priori, despite being popular as drug candidates, for similar reasons; most cancers will have multiple “tricks up their sleeve” and attacking one tumor-specific marker won’t necessarily reach a large proportion of tumor types or produce sustained results.
Dunn, Gavin P., Lloyd J. Old, and Robert D. Schreiber. “The immunobiology of cancer immunosurveillance and immunoediting.” Immunity 21.2 (2004): 137-148.
Waldhauer, Inja, and Alexander Steinle. “NK cells and cancer immunosurveillance.” Oncogene 27.45 (2008): 5932-5943.
Dunn, Gavin P., Lloyd J. Old, and Robert D. Schreiber. “The three Es of cancer immunoediting.” Annu. Rev. Immunol. 22 (2004): 329-360.
Khong, Hung T., and Nicholas P. Restifo. “Natural selection of tumor variants in the generation of “tumor escape” phenotypes.” Nature immunology 3.11 (2002): 999-1005.
Huang, Bo, et al. “Toll-like receptors on tumor cells facilitate evasion of immune surveillance.” Cancer research 65.12 (2005): 5009-5014.