Patients with cancer have detectable numbers of T cells in their blood that recognize tumour-associated antigens, yet this rarely corresponds with effective tumour eradication, even after tumour-vaccine-induced increases in cytotoxic T-cell numbers. Curiel and colleagues now show that regulatory T cells might be one factor that prevents an effective antitumour response.
Recent studies have indicated that when self-recognizing T cells are present, regulatory T cells become activated and shut down the antitumour response. Curiel and colleagues studied the profile of tumour-associated T cells in patients with advanced ovarian cancer and found that 10–17% of T cells isolated from the tumour ascites were regulatory T cells (CD4+CD25+). Furthermore, about 23% of the T cells identified in the tumour tissue itself were of the regulatory subtype, with the percentage of these cells increasing as disease progressed. Regulatory T cells were undetectable in normal ovarian tissue sections, however.
But what effect do regulatory T cells have on the antitumour immune response? The authors showed that regulatory T cells isolated from human tumour ascites inhibited the proliferation of autologous tumour-specific cytotoxic T cells in a mouse xenograph model of ovarian cancer. And although injection of tumour-specific cytotoxic T cells delayed tumour growth, this effect was inhibited by the co-injection of regulatory T cells.
What might attract a regulatory T cell into the tumour tissue? Regulatory T cells are normally localized in lymph nodes, but surprisingly, there were fewer regulatory T cells in tumour-draining nodes than in lymph nodes from patients without cancer. Indeed, with increasing cancer progression, the levels of regulatory T cells decreased in the lymph nodes and increased within the tumour tissue and ascites, indicating that regulatory T cells might be actively recruited from these sites by tumour-produced chemotactic factors. The authors examined a number of candidate chemokines and showed that CCL22, produced by both macrophages and tumour cells, attracts regulatory T cells, which express the CCL22 receptor CCR4. An antibody against CCL22 prevented trafficking of regulatory T cells to human ovarian tumours in the xenograft model.
Finally, Curiel and colleagues correlated regulatory T-cell numbers with patient prognosis — a review of 70 patients with ovarian cancer confirmed that the greater the number of tumour-associated regulatory T-cells, the more adverse the prognosis for all tumour stages. The authors conclude that inhibiting the function of regulatory T cells, or perhaps blocking tumour chemokine signalling to inhibit their migration, could improve the efficacy of many antitumour vaccines.
ORIGINAL RESEARCH PAPER
Curiel, T. Y. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune pivilege and predicts reduced survival. Nature Med. 10, 942–949 (2004)
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McCarthy, N. Deregulation required?. Nat Rev Cancer 4, 754 (2004). https://doi.org/10.1038/nrc1468
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DOI: https://doi.org/10.1038/nrc1468