“Our experiments using lymphoma, a type of blood cell cancer, uncovered a two-step process that revolves around two receptors found on different types of immune cells, linking those cells to antibodies. In this way, these so-called Fc receptors act as crucial intermediaries,” says Jeffrey Ravetch, Theresa and Eugene M. Lang Professor and head of the Leonard Wagner Laboratory of Molecular Genetics and Immunology.
“These findings suggests ways current anticancer antibody treatments might be improved, as well as combined with other immune system stimulating therapies to help cancer patients,” Ravetch says.
Antibody-based therapies, in which patients receive immune proteins that target specific proteins, called antigens, produced by their tumors, have been available for about two decades. Previous work in the lab has shown that these antitumor antibodies bind to Fc receptors on activated immune cells, prompting those immune cells to kill the tumor. However, it was unknown which Fc receptor was involved, or how the tumor killing led the immune system to generate memory T cells against these same antigens, in case the tumor producing them should return.
Ravetch and first author David DiLillo, a postdoc in the lab, broke down the process by injecting lymphoma cells that expressed the antigen CD20 into mice with immune systems engineered to contain human Fc receptors. When these mice received antibodies that
targeted CD20, they all survived. Three months later, most of the same mice survived being challenged again with the same lymphoma or a different one that also expressed CD20. Mice not treated with antibodies, or those that received non-CD20 lymphoma the second time around, did not fare well.
Different types of immune cells can express different Fc receptors. So, based on the cells Ravetch and DiLillo thought were involved, they looked to the Fc receptors expressed by cytotoxic, or cell killing, immune cells, that carried out the initial attack on tumors, and the Fc receptors found on dendritic cells, which are crucial to formation of memory T cells.
To test the involvement of these receptors, the researchers altered the therapeutic antibodies delivered to the lymphoma-infected mice so as to change their affinity for these Fc receptors. Then, they looked for changes in the survival rate of the mice after the first challenge with lymphoma, and then again after a second.
When they dissected this process, they found two steps: One Fc receptor, known as FcRIIIA, found on a Pac-Man-like immune cell known as a macrophage, responds to the antibodies, and prompts the macrophage to engulf and destroy the antibody-laden tumor cell. These same antibodies, still attached to tumor antigens, activate a second receptor, FcRIIA, on dendritic cells, which use the antigen to prime T cells. The result was the generation of a T cell memory response that protected the mice against future tumors expressing CD20.
“By engineering the antibodies so as to increase their affinity for both FcRIIIA and FcRIIA, we were able to optimize both steps in this process,” DiLillo says. “Current antibody therapies are only engineered to improve the immediate killing of tumor cells, but not the formation of immunological memory. We are proposing that an ideal antibody therapy would be engineered to take full advantage of both steps.”
It is important to note that the immunological memory at the center of this study had a significant limitation: It protects only against tumors that express the specific antigen targeted by the antibodies that are administered.
“Because cancer can be highly unpredictable, and can reoccur in altered forms, we think an important next step may be boosting the antitumor immunity by combining antibody therapy with other, new immunological therapies that can, for example, enhance T cell responses,” Ravetch says.
|Cell 161, 1–11 (online May 11, 2015)
Differential Fc-Receptor Engagement Drives an Anti-tumor Vaccinal Effect
David J. DiLillo and Jeffrey V. Ravetch