Most of the tumour antigens that have been identified are abberantly expressed self-molecules that are poorly immunogenic. This realization, together with the fact that normal individuals have T cells that react against self-antigens, but are held in check by peripheral-tolerance mechanisms, has resulted in attempts to develop anti-tumour therapies that stimulate these anti-self T cells and elicit anti-tumour responses. A new study in the Journal of Clinical Investigation shows that stimulating the homeostatic proliferation of a polyclonal population of adoptively transferred T cells — including those that are specific for tumour self-antigens — in lymphopaenic animals can induce anti-tumour immunity.

Mice with lymphopaenia (induced by sublethal irradiation) and wildtype mice were challenged with a subcutaneous injection of melanoma cells, and tumour growth was assessed after 52 days. The lymphopaenic mice developed smaller tumours than wildtype mice. This anti-tumour effect was enhanced in a dose-dependent manner by the adoptive transfer of syngeneic lymph-node T cells before challenge with the tumour cells. In vitro testing of the homeostatically expanded T cells showed that they specifically recognised the melanoma tumour cells, but not unrelated colon carcinoma cells.

Next, the authors investigated whether T-cell clonal expansion per se was sufficient to induce the anti-tumour response or whether antigen presentation of tumour antigens was also important. The inhibition of tumour growth was more efficient in wildtype lymphopaenic mice transfused with T cells and challenged with melanoma than in lymphotoxin-α-deficient mice, which lack lymph nodes. When T cells that cannot traffic through lymph nodes (because they do not express β7-integrin or L-selectin) were transferred, they were much less effective than normal T cells at eliciting the anti-tumour response. Together, these results show that the proliferating T cells need to be exposed to tumour antigens that are presented in the lymph nodes.

When mice that had rejected the melanoma cells were rechallenged with either melanoma or colon carcinoma cells, they again rejected the melanoma, but not the colon carcinoma, tumours, which indicates that the T-cell homeostatic proliferation had resulted in the development of specific long-term anti-tumour immunity.

Could homeostatic proliferation be useful for the treatment of established tumours? Lymphopaenic mice were challenged with melanoma cells, and when the tumours reached a specific size, the mice were transfused with lymph-node cells. Tumour growth was markedly inhibited in treated mice compared with controls.

These data indicate that, in the clinic, it might be beneficial to begin tumour immunotherapy soon after the completion of chemotherapy to induce effective homeostatic T-cell proliferation.