Coley's Toxins Revisited
by Roberto
In the last few years, immunotherapy has quickly become the emerging "fourth pillar" in cancer treatment, joining surgery, radiation therapy and chemotherapy. The basic concept behind the development of immune checkpoint inhibitors as anti-cancer therapeutics is that activating the immune system can sometimes result in the body ridding itself of malignant cells. Such activation immunotherapy shows much promise. The first checkpoint inhibitor (a monoclonal antibody) was approved for human use in 2011. Since then, many other such therapeutics have undergone development and are currently used to treat a multitude of cancers. Thus, it was no surprise when the 2018 Nobel Prize in Physiology and Medicine went to James Allison and Tasuku Honjo "for their discovery of cancer therapy by inhibition of negative immune regulation."
Fig. 1. Frontispiece of Coley's 1895 publication. Source. Frontispiece: Colorized scanning electron micrograph of Streptococcus pyogenes (yellow) and a human neutrophil (blue). Credit: NIAID. Source
These recent and very exciting advances could lead one to believe that cancer immunotherapy is something entirely from the twenty-first century. But the concept of activating the immune system to fight cancerous cells goes back to the waning years of the nineteenth century. During that time, the New York-based bone surgeon William Coley met a patient who had had a severe inoperable malignancy and was now in complete remission. The one oddity in that clinical case was that the patient had suffered a bacterial infection at the time of cancer diagnosis. This led Coley to survey the literature for anecdotal evidence associating inoperable tumor remissions with the incidence of fevers and infections. He was taken by several accounts that linked the occurrence of erysipelas – bacterial infections of the superficial layer of the skin – with tumors that "miraculously" disappeared. Coincidentally, around this time Streptococcus pyogenes was identified as the causative agent of erysipelas. So, Coley began injecting his cancer patients with the bacterium. Using live bacteria proved a bit too harrowing and dangerous for the patients, causing high fevers and sometimes even death. He thus opted for heat-killed bacteria. Through many years of trying different combinations on many patients, he finally settled on preparations of heat–killed S. pyogenes and Serratia marcescens. These became known as Coley's Toxins. Despite the reasonable success of his therapies, many physicians remained skeptical. As radiation therapy and chemotherapy approaches gained momentum along the twentieth century, the use of Coley's Toxins decreased. By 1962, their clinical use was essentially banned by the U.S. Food & Drug Administration (FDA). Nonetheless, today William Coley is referred to as the "Father of Immunotherapy." (If you are a history buff like I am, you'll enjoy this historical treatment of the subject.)
Fig. 2. The membranes of S. pyogenes contain the cardiolipin SpCL1, which specifically activates dendritic cells via the TLR2-TLR1 pathway, leading to the production of proinflammatory cytokines TNF‑α, IL‑6, IL-12p40 and IL-23. Source
What is it about S. pyogenes that causes an activation of the immune system? Perhaps if there is a specific component responsible, it might prove useful in the development of additional cancer immunotherapies. With this as a possible incentive, but surely also driven by the curiosity for answering this long-standing question, Yern-Hyerk Shin and collaborators from the groups of Jon Clardy and Ramnik Xavier, set out to purify immunogenic molecules from this bacterium. Their results are a perfect example of how the bread-and-butter chemistry approaches of activity-guided purification and structure elucidation yield clear-cut answers to questions in biology. The authors first developed a cell-based assay – using murine bone-marrow-derived dendritic cells – that allowed them to measure the production of proinflammatory cytokines. They then extracted small molecules from the bacterial cells and their culture supernatants and fractionated these using reverse phase and size exclusion chromatography. They discovered a single, cell-associated molecule with immunogenic activity. Using the standard tools of the trade – mass spectroscopy, one- and two-dimensional NMR, etc., etc., – and based on their cumulative decades of experience the authors determined the structure. The molecule is a cardiolipin, which they named SpCL‑1, with two stearic acid and two oleic acid side chains. To really nail it down, they synthesized the molecule from scratch along with a similar cardiolipin with switched acyl chains. Only the synthetic molecule identical to SpCL‑1 had immunogenic activity. Having the immunogen on hand, they next asked what signaling receptors (Toll-Like Receptors, or TLRs) were used for the immune activation by SpCL‑1 and which proinflammatory cytokines were produced. They got clear answers. The SpCL‑1 receptor is the TLR1-TLR2 heterodimer and TNF‑α, IL‑6, IL-12p40 and IL-23 are the cytokines induced.
Will SpCL‑1 become useful in the development of future cancer immunotherapies? That answer remains in the future. It could be a good starting place in the synthesis of small molecules with specificity that might someday replace monoclonal antibodies. In addition, the finding of this bacterial cardiolipin's immunomodulatory activity could have implications for the etiology of autoimmune diseases such as rheumatic fever and lupus. These diseases are associated with anticardiolipin antibodies. Thus, they could start with the activation of autoreactive T‑cells by cross-reactive bacterial cardiolipins. In their closing comments, the authors project a very healthy perspective: "Even if SpCL‑1 never becomes therapeutically useful, it identifies a plausible molecular mechanism for a historically prominent cancer treatment, and some poorly understood autoimmune diseases." Stunning work wonderfully understated.
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