Preventing escape

One important aspect of tumour development is the ability of cancer cells to escape detection and destruction by the host immune system. Gabriel Rabinovich and colleagues provide evidence that mouse melanoma cells express a T-cell inhibitor called galectin-1 (Gal1), which could be a useful therapeutic target.

Gal1 — a carbohydrate-binding protein with regulatory functions — is expressed by many different tumour types. Increased expression of Gal1 has been correlated with tumour aggressiveness and metastasis. The authors studied its function by transfecting B16 mouse melanoma cells — which express high levels of Gal1 — with Gal1 antisense cDNA to establish knockdown clones. These clones expressed either low or intermediate levels of Gal1. Conditioned medium from wild-type B16 cells induces high levels of apoptosis when it is applied to T cells in vitro, whereas conditioned medium from the Gal1 knockdown clones induced only low levels of T-cell apoptosis.

In mice, tumour growth from clones that expressed intermediate levels of Gal1 was substantially delayed, compared with wild-type melanoma cells. Furthermore, cells that expressed low levels of Gal1 were rejected. As all clones grew at the same rate in immunodeficient mice, components of the immune system must be responsible for these different responses. The authors went on to show that tumour rejection induced by Gal1 blockade required intact CD4⁺ and CD8⁺ T-cell responses.

In previous studies the authors had shown that Gal1 specifically suppresses the T-helper 1 (T_H1) immune response, so they looked to see if this response occurred in mice injected with the Gal1-knockdown melanoma cells. Tumour-draining lymph nodes were removed from these mice and ex vivo stimulation of their immune cells resulted in increased levels of the T_H1 cytokines interleukin-2 and interferon-γ, compared with controls. So, blocking Gal1 production by melanoma cells restores the ability of the host immune system to initiate a T_H1 response. The Gal1-knockdown melanomas were also observed to be infiltrated with mononuclear cells, and T cells from these mice were less susceptible to apoptosis.

These mice eventually rejected the Gal1-knockdown cells. Furthermore, when they were rechallenged with wild-type B16 melanoma cells tumour growth was delayed, compared with naive mice challenged with B16 cells. So, inhibition of Gal1 expression not only enhances T_H1 tumour-specific immune responses, it also provides resistance to subsequent challenge with Gal1-expressing tumour cells. This work provides an important new link between Gal1 and tumour progression, and identifies an important mechanism that contributes to immune privilege of tumours.