A Ludwig Cancer Research study has uncovered how a broad variety of tumor cells thwart attack by killer T cells of the immune system by coating them with what amounts to a molecular glue. The study, which was led by Pierre van der Bruggen of the Brussels Branch of the Ludwig Institute for Cancer Research, details how the glue in question—a naturally occurring protein named galectin—stops activated T cells that are primed and ready to kill cancer cells from triggering their attack. Published in the current issue of Nature Communications, their findings suggest a novel target for cancer therapy. The findings also have significant implications for how oncologists and researchers developing immunotherapies assess T cells found in tumors.
“We’ve known for some years that T cells isolated from tumors are not very efficient in killing their targets,” says van der Bruggen. “We knew also that these T cells are covered with galectins secreted primarily by cancer cells that impair the mobility of important receptors on the T cell surface. But we didn’t know what role exactly galectin played in the T cell dysfunction we were seeing.”
Galectin is a protein produced at high levels by a broad range of cancer cells, including those from pancreatic, ovarian and colon tumors. van der Bruggen and his colleagues have previously shown that removing galectin from T cells with an antibody or other chemicals can turn lethargic T cells isolated from tumors into cancer cell-killing machines again.
The researchers hypothesized that galectin, which binds sugar molecules that are typically attached to cell-surface proteins, was preventing the activation of the T cell receptor (TCR). This receptor recognizes little bits of aberrant proteins held out by sick and cancerous cells. But when van der Bruggen and his colleagues conducted studies on T cells as they targeted cancer cells—rather than on the T cells in isolation—they quickly realized the TCR was unimpeded by galectin.
The activated TCR sends signals that prompt the production of cytokines—factors that help amplify the immune response—and the secretion of toxic granules that kill the target cell. “We were very surprised to see that TCRs on T cells coated with galectin could in fact be activated and produce cytokines within the cell,” says van der Bruggen. “But the cells were unable to trigger their release.”
A series of elegant microscopic and biochemical analyses conducted mainly by Anne-Elisabeth Petit, a Ph.D. candidate in van der Bruggen’s lab, eventually revealed why. Galectin, it turns out, gums up a protein known as LFA-1, which is supposed to reach out and bind a protein in the target cell, and so tighten the T cell’s bond to its target.
LFA-1 was already known to be important for the initiation of the T cell attack. The current study shows that it also appears to help trigger the final stages of that assault, clearing a passage out of the T cell for toxic granules and cytokines through a complex of proteins around the TCR known as the “immunological synapse”. The researchers show that blocking LFA-1 using antibodies has the same effect on the T cells’ release of cytokines and toxic payloads as galectin. Removing galectin has the opposite effect on malfunctioning T cells.
The study has two significant clinical implications. It indicates that the method of assessing the function of tumor-infiltrating T cells—measuring the production of cytokines, not their release—is prone to misleading false positives. It also suggests that drugs that counter galectin may potently boost immunotherapies that activate T cell responses, such as checkpoint blockade, which releases the brakes on T cell activation.
“We have a mechanism for T cell activation that has nothing to do with checkpoint inhibition, but which could be perfectly complementary to those therapies,” says van der Bruggen. He and his colleagues are already working on developing such therapies.
This work was supported by Ludwig Cancer Research, WELBIO, Fondation contre le Cancer, the Fonds de la Recherche Scientiﬁque Médicale-TELEVIE & FRSM, the Belgian Programme on Interuniversity Poles of Attraction, BELSPO and by a gift from the Delori family.