There's good evidence that killer T cells (aka cytotoxic T cells or CTL's) are the main weapons employed by the immune system to protect us against tumors. Consistent with that, people are often found to carry killer T cells directed against the tumors that they harbor. However, it wasn't clear for a long time how such T cells got to carry out that function. Recall that the function of killer T cells is to destroy cells carrying a protein fragment on its surface, a fragment nestled in the arms of a class one major histocompatibility complex protein (MHC I). Remember these pieces of protein got there via the proteosome, the apparatus present in cells whose function is to digest internal proteins. Since most types of cancer cells are not good at antigen presentation, they're not particularly good at fulfilling these functions and thereby are ineffective at signalling to killer T cells that they've become malignant. On the other hand the class two MHC's (MHC II) are specialized to detect proteins (mostly viruses) outside of cells. As such, they are capable of detecting the proteins on tumors, but their function is to present them to helper T cells, not killers.
The solution to this conundrum is a phenomenon called "cross presentation". Apparently, there is a class of antigen presenting cells - a subset of dendritic cells – that can take up proteins from tumors and load them onto MHC I molecules, thereby presenting them to killer T cells. In turn, these assassins can destroy the cancer. However, as evidenced by the numbers of people who succumb to the disease, this attack doesn't always succeed in part because tumors may elude it.
Cancer cells can evade the immune response in many ways. One common mechanism that they employ is to increase the synthesis and accumulation of two proteins – CTLA-4 (cytotoxic T lymphocyte antigen 4) and PD-1 (programmed death-1). Both these molecules work to inhibit T cell activation, a process that requires both T cell receptor binding to an antigen and co-stimulation by a dendritic cell (The illustration at the right shows CTLA-4 in action. It binds to the B7 receptor that is normally used to activate the T cell. PD-1 performs a similar inhibitory function, but works by binding to a protein found on tumor cells that helps cause T cells to commit suicide). Normally, these two proteins serve as checkpoints, preventing autoimmunity and excessive inflammation associated with uncontrolled T cell activation. Tumors are clever. They subvert these functions to limit their susceptibility to immune attack. Naturally, scientists who study these processes thought to inhibit the inhibitors, thereby coming up with a therapy that is called "checkpoint blockade". I was intrigued to discover that the first such therapies were suggested more than 20 years ago. Since then much has been learned, as I discuss below.
In 1996, James Allison's laboratory reported that antibodies directed against CTLA-4 had a dramatic effect on controlling tumors in mice. Their findings spurred a rash of trials and, eventually, marketed pharmaceuticals. And just this year, Allison was awarded a portion of the Nobel Prize in Physiology or Medicine for his discoveries. Today, anti-CTLA-4 monoclonals have been approved for treating advanced melanoma. Monoclonal antibodies directed against PD-1 have proven even more effective and have been approved for treating melanoma, lung, kidney, bladder, and colon cancer. A combination of the two therapies has yielded improved results in some cases. Checkpoint blockades have become one of the major weapons in the battle against cancer. However, the news has not been all rosy. About half of all patients treated with antibodies against CTLA-4 and PD-1 fail to respond. Or, after responding, relapse. In addition, these therapies are not without risk - many patients develop autoimmune reactions, some quite serious, as a result of treatment.
A couple of nagging questions came to me after reading about checkpoint blockade and T cell killing of tumors. The first one was rather basic. Why do T cells respond to cancer cells at all? Since tumor cells are simply normal cells that have gone awry, why does the immune system attack them? I offered some answers in a previous post. One reason that has been offered is that cancers carry a burden of "neoantigens", that is, proteins that are unusual (not self) that result from the mutations that are essential for the expansion of tumors. These aberrant proteins appear foreign to the immune system and may generate a response. How common are these neoantigens? Intriguingly, it depends on the type of cancer. Melanomas and lung cancers carry, on average, something on the order of 10 mutations per million bases of DNA (the human genome size is 3 billion base pairs) and this is strongly correlated with the generation of neoantigens. By contrast, other kinds of cancer, including leukemias of various kinds, bear 10 or 20 times fewer mutations. Why this difference? I'm not sure, but it seems likely that the lungs of smokers and the skin of people exposed to the sun are subjected to agents that can cause many mutations – not only ones that can cause cancer, but base changes in incidental genes (bystanders) that can generate neoantigens.
In the posts that follow, I will finally get to my main interest in developing this blog: chimeric antigen receptors, part of what has been termed "adoptive cell therapy". Hang in there. The end is near.