Scientific Method / Science & Exploration

Healthy neighboring cells cut down immune response to tumors

Healthy cells in a tumor's microenvironment protect the tumor by suppressing …

It has been known for almost twenty years that tumor cells express and present antigens that can elicit an immune response. So why doesn’t our immune system destroy them? It had been suggested that cancers somehow induce tolerance or become less immunogenic as they grow, but neither of these ideas has withstood experimental scrutiny. The fact that a foreign tumor can be implanted into an animal but is not rejected by the host’s immune system suggests that the tumors are probably inducing some of the host's cells to produce the tolerance.

Stromal cells—normal cells in the connective tissue that typically surrounds a tumor—are well positioned to undercut the immune response. A specific type of stromal cell has been implicated in immune suppression in other contexts; these cells are characterized by their expression of fibroblast activation protein-α (FAP). 

To determine if these FAP+ cells modulate the immune response to tumors, researchers made mice in which they can turn off FAP expression in stromal cells. They then performed this shutdown after lung cancer cells had been injected and allowed to grow into tumors. 

Lung carcinoma cells were injected into these mice and allowed to grow into tumors, and then FAP expression was turned off. Once it was shut down, a vaccine against the cancer cells completely suppressed tumor growth. Even in the absence of the vaccination, tumor growth halted when FAP was turned off. Thus, the loss of FAP+ stromal cells seems to enable the tumor to induce an immune response that causes its growth to arrest.

To begin to uncover how this might work, they examined different types of immune cells. FAP+ cell ablation did not result in a change in T cell populations. However, the tumor growth arrest seen in FAP deficient mice was reversed by the administration of antibodies against tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ), molecules that can induce necrosis. The expression of these cytokines remained unchanged in these mice, which suggests that the FAP+ stromal cells probably reduce cellular responses to them, protecting the tumor cells from necrosis.

FAP+ cells have also been linked to cells involved in wound healing; it is almost as if they treat a tumor as a chronic, nonhealing wound. The authors note that, from this perspective, immune suppression by FAP+ stromal cells can be viewed as “a developmentally programmed, tissue protective function that, in the context of a tumor, is catastrophically inappropriate.” 

Cancer therapies are increasingly focused on strengthening the immune system, rather than killing the tumor directly, as traditional chemotherapies have done. Interfering with immunosuppression by FAP+ stromal cells may become part of this new arsenal of cancer immunotherapy.

Science, 2010. DOI: 10.1126/science.1195300  (About DOIs).

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