This story is pretty damn cool. It’s been the top article on the website for the Proceedings of the National Academy of Sciences since I started this blog, and I’ve wanted to take a look at it for a while. Basically, what these researchers out of Stanford found is that when the surface molecule CD47 is blocked on cancer cells, the body’s macrophages will eat them. That in and of itself is pretty nifty, but the paper examines whether or not this phagocytic response can trigger a full adaptive immune, which would be a huge leap forward in cancer treatment.
Previous studies have found that anti-CD47 monoclonal antibodies, that is, antibodies specifically cloned to block CD47, can help to trigger aggressive phagocytosis against a wide range of cancer types, from leukemia and lymphoma to solid cancers such as bladder, breast, or prostate cancer. These cancers were xenografted from humans into immunodeficient mice, as were all of the cancers studied in this paper. So this group took the idea one step further, and found that in fact yes, these phagocytes can trigger the body’s adaptive immune response, at least to some degree.
So first some basics, to explain how all of this works. CD47 is a molecule that appears on the surface of a wide variety cells and functions in a number of different processes. In many normal cell lines and a number of tumor types, activation of CD47 leads to apoptosis, or programmed cell death, but in many other cancers, activation will actually lead to proliferation. The difference in functionality is based largely on what molecule it interacts with and any associated proteins that may work with it in specific cell types. For the purposes of this study though, it acts as a “don’t eat me” signal to the body’s macrophages (which is actually what the paper calls it, in case you were wondering), staving off the body’s innate defenses.
In the cancers studied, when CD47 is blocked other signal molecules that encourage phagocytosis dominate, and so a macrophage will consume tumor cells. Cancer is a profoundly clever disease, which works to evade all inborn routes to cell death. Producing fully functional CD47 is one of the many ways that cancer can evade detection and destruction and in fact it is often over-expressed on tumor cells. This both helps to evade phagocytosis and to trigger further proliferation in many contexts.
By introducing antibodies that are specially designed to bind CD47 and block its interaction with macrophage surface proteins, researchers found they could induce phagocytosis of cancer. Basically, you’re immune system would eat and digest the cancer cells. The question then became could this trigger an adaptive response, that is, a response specific to these tumor cells, or was it limited to the nonspecific response of macrophages? The study found that the process could trigger at least part of the body’s adaptive immune system.
By labeling both T cytotoxic cells and T helper cells, the researchers could track activation and subsequent proliferation of both types of T cell in response to phagocytosis. Ideally, the macrophages would trigger both types to proliferate, creating an adaptive response in both the T cytotoxic cells and the helper cells, which would then trigger B cells to produce antibodies and further strengthen the immune reaction. Unfortunately, what they found was that only cytotoxic cells were activated by their macrophages. This means that while they could create a potent cytotoxic response, they couldn’t trigger the other half of the adaptive immune system, in particular the antibody producing B cells, which would further the specificity of the response and increase the number of cell types involved in the overall result. This cytotoxic response would allow for limited action that would target specific antigens on the surface of the cancer cells and thus facilitate targeted killing.
Despite lacking a T helper response, this is still a huge find in cancer medicine. Even activating a part of the adaptive immune response promises a huge impact on clinical results. Along with those improvements, developing new ways to utilize these findings could potentially uncover other ways to more completely activate the adaptive response, aiding in the overall fight against cancer. Cancer is such a dangerous adversary because it is, at its core, your body, but twisted, a distorted version of the self. Findings like this though, are working towards taking the body back. Which is really quite cool.
Original article: http://www.pnas.org/content/110/27/11103.short?rss=1&%3bssource=mfr