Editors' ChoiceCancer

Focusing downstream for safer immunotherapy

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Science Translational Medicine  01 Jul 2015:
Vol. 7, Issue 294, pp. 294ec109
DOI: 10.1126/scitranslmed.aac8102

Immunotherapy has taken center stage in the fight against cancer. Conventional therapies often induce resistance by selecting for a subset of tumor cells with stem-like properties. Promising new tumor immune targets with high potential are emerging, and these can be combined with traditional chemotherapy regimens to overcome tumor resistance and fight tumor progression and metastasis. However, a major roadblock hindering development of these therapies is toxic side effects from global targets that impair normal immune function. The key to overcoming this roadblock may be downstream targets that regulate fewer critical immune mechanisms, yet still target major tumor-promoting pathways.

A recent study by Kitamura et al. presents compelling data to support this idea. The authors studied metastasis-associated macrophages (MAMs), which are recruited to tumors by CC-chemokine ligand 2 (CCL2). Unfortunately, CCL2 blockade has not been effective in humans because of feedback loops creating toxicity. However, the authors found that CCL2 signaling stimulated CCL3 secretion in MAMs to promote pulmonary metastasis of breast cancer cells. Genetic ablation of CCL3 or its receptor CCR1 markedly reduced the number of MAMs and the burden of lung metastasis in mice. Conversely, CCR1 signaling enhanced the attachment of MAMs to tumor cells and increased retention of these cells in the tumor microenvironment. Moreover, introduction of wild-type MAMs into CCL3-deficient mice restored metastasis, whereas CCR1 deficiency prevented MAM accumulation and reduced the interaction of MAMs with tumor cells. As distal components of the CCL2 pathway, CCL3 and CCR1 may be effective targets for reducing breast cancer metastasis because they regulate relatively few global immune functions.

The CCL3/CCR1 metastasis-promoting function is likely to be relevant in multiple cancers and may be a prime example of a downstream target that could effectively inhibit a detrimental immune cell response while minimizing toxic side effects.

T. Kitamura et al., CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J. Exp. Med.10.1084/jem.20141836 (2015). [Abstract]

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