Smouldering beneath many latent tumours is a chronic inflammation that goads pre-malignant cells into becoming full-blown cancer. The spark that kindles these flames comes from an unexpected source.
Chronic inflammation makes individuals susceptible to many forms of cancer. The culprits that drive this process are inflammatory cells and signalling molecules of the ‘innate’ immune system — our in-born defence system, which recognizes potential threats without previous exposure to them. But in a surprising twist, de Visser et al., writing in Cancer Cell1, demonstrate that specialized cells from the ‘adaptive’ immune system orchestrate the innate inflammation that promotes tumour progression.
The link between inflammation and the promotion of cancer was first observed in the nineteenth century2, but only in recent years has it become a generally accepted phenomenon2,3,4. Epidemiological studies have shown that chronic inflammation predisposes individuals to certain cancers, and conversely that non-steroidal anti-inflammatory agents protect against several tumours. Most precancerous and cancerous tissues show signs of inflammation; this involves the movement of innate immune cells into the tissue, the presence of specific inflammatory signalling molecules (called cytokines and chemokines), changes in tissue structure (remodelling), and the formation of new blood vessels (angiogenesis).
Further studies found that cancer-associated inflammation actually promotes tumour growth and progression2,3,4,5,6. For instance, innate immune cells called tumour-associated macrophages work their way into precancerous tissue, and can release factors that promote tumour growth and metastasis2,7. Accordingly, in many human tumours, the infiltration of large numbers of these macrophages is associated with poor prognosis. Moreover, increased expression of genes associated with macrophage infiltration (such as CD68) forms part of the molecular signatures that herald poor prognosis in certain cancers8.
The best-studied examples of inflammation-associated cancer are colon cancer and cervical carcinoma. Cervical carcinoma is caused by infection with human papilloma virus (HPV). Genetically engineered mice that carry some of the genes of HPV strain 16 — targeted to be expressed in the skin epithelial tissue that gives rise to carcinomas — recapitulate many of the stages of this disease. Innate immune cells, most prominently mast cells and granulocytes, infiltrate the pre-malignant epithelial tissues, and they are followed by macrophages as the cancer develops further (Fig. 1). Innate immune cells drive a chronic inflammatory process that promotes overproliferation of epithelial cells, tissue remodelling and angiogenesis, followed eventually by invasive carcinoma9.
Using the HPV16 mice, de Visser et al.1 examined the interplay between innate and adaptive immunity in the progression of these tumours. They bred the HPV16 mice with mice that lack both types of adaptive immune cell — T cells and B cells. This genetic elimination of adaptive cells blocked the recruitment of innate cells, and the subsequent tissue remodelling and angiogenesis. Carcinogenesis was therefore arrested at the stage of epithelial overproliferation. When B cells from HPV16 mice were transferred into the immune-deficient HPV16 cross-breed animals, the expected inflammatory response and cancer progression were restored, showing that these cells are the perpetrators.
B cells do not infiltrate the precancerous tissues, and so they must orchestrate the innate immune cells remotely. This was confirmed by the finding that blood serum (without cells) from HPV16 mice also reinstated cancer progression in the HPV16 cross-breed mice. But what is the remote-control mechanism that links B cells with the innate immune response? One possibility is antibodies, which are produced by B cells. Indeed, de Visser et al. found preliminary circumstantial evidence that antibodies may drive the cancer-promoting inflammation (Fig. 1).
These results are surprising and provocative. In a context in which adaptive immunity promotes inflammation, one would expect T cells to be the prime mover, but this is clearly not the case here. Moreover, de Visser et al. found that the B-cell antibodies, rather than occurring next to the overproliferating epithelial cells, were in fact found in the underlying dermis layer. This argues against the possibility that the antibodies trigger immune responses by recognizing molecules on the surface of the tumour cells. The extracellular milieu surrounding tumours can contain peculiar components10,11, and de Visser et al. speculate that cancer-associated changes in this milieu may elicit the antibody response that kindles the innate immune response. Immune complexes in the local tumour environment would then activate innate immune cells to sustain chronic inflammation and further tumour progression.
Overall, de Visser and colleagues draw attention to the poorly explored issue of the interplay between the innate and the adaptive arms of immunity — on the one hand in surveillance against cancer by T cells12, and on the other in inflammation-driven cancer promotion. It will be necessary to show definitively that antibodies are indeed the molecular messengers that allow B cells to control the innate immune response, and to define their specificity. Moreover, whether B cells have a general role in controlling the chronic inflammation associated with other types of cancer, and the mechanism involved (for example, requirement for T-cell help and molecules recognized by antibodies), should also be assessed. Therapeutic targeting of cancer-promoting inflammatory reactions is in the early stages of development4, and its progress will depend on defining the underlying cellular and molecular mechanisms in the relevant systems.
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