Immune tolerance is promoted by regulatory T (TReg) cells, which require signalling from the chemokine receptor CCR7 for their activation and function. However, the role of CCR7 in immune responses to tumours is less clear, as exogenous CCR7 ligands have been shown to promote both tumour immune suppression and anti-tumour immunity. Therefore, the authors investigated the effects of endogenous secretion of one CCR7 ligand, CCL21, from melanomas in vivo. Mouse melanoma cells expressing low, normal or high levels of CCL21 (accomplished by short hairpin RNA knockdown of CCL21, scrambled short hairpin RNA control and CCL21 overexpression, respectively) were implanted into syngeneic mice. Tumours expressing low levels of CCL21 (CCL21low) were significantly smaller than those expressing high (CCL21high) or normal levels. The differences in growth did not seem to be a result of autocrine CCL21–CCR7 signalling in the tumour cells, and were dependent on the host mice expressing CCR7. Furthermore, when both CCL21low and control tumours were implanted on opposite shoulders of the same mouse, the CCL21low tumours grew to the same size as controls, demonstrating that modification of the host response by the control tumours allowed the CCL21low tumours to grow.
How does CCL21–CCR7 signalling affect the host response to tumours? The CCL21-expressing tumours attracted more T cells overall than CCL21low tumours, but CCL21low tumours contained higher T cell densities, more cytotoxic T cells specific for melanoma antigen and more cytokines associated with anti-tumour immunity. Conversely, CCL21high tumours had more TReg cells and increased levels of transforming growth factor-β1 (which promotes tumour tolerance). In addition, CCL21 expression increased CCR7-dependent attraction of tumour-promoting myeloid-derived suppressor cells. Examination of the stroma in CCL21-expressing tumours revealed several features similar to lymph node stroma that are important for maintaining peripheral tolerance, including increased numbers of lymphoid tissue inducer (LTi) cells, which promote lymphoid neogenesis. Recruitment of LTi cells was dependent on host CCR7 expression, and mice lacking LTi cells were unable to support CCL21-induced tumour growth.
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