Immunotherapy, or harnessing the immune system to target cancer cells more precisely, is one of the most promising new areas in cancer research and treatment.
And yet, when it comes to colorectal cancer, the leading cause of cancer death in men under age 50 and the second-leading cause of cancer death in men and women overall, immunotherapy has faltered.
"In order to use the immune system, you need to have immune cells in the tumor," explained Silvia Guglietta, Ph.D., an immunologist at MUSC Hollings Cancer Center. "In colon cancer, especially in the metastatic stage of colon cancer, only 5% of these cancers have immune cells in the tumor – which means that basically over 90% of patients cannot be treated with immunotherapy."
Most colon cancers are "cold" tumors, meaning there's little reaction from the immune system. Guglietta's research focuses on this perplexing idleness from the immune system and how to transform a cold tumor into a "hot" tumor teeming with attacking immune cells.
Now, she has been awarded a four-year $960,000 American Cancer Society Research Scholar Grant to pursue this question.
The ACS Research Scholar Grant is highly competitive. Guglietta was especially pleased to hear that her proposal was one of the top-scoring contenders in the study section. Furthermore, she is pleased that her funded research is a continuation of an ACS Institutional Research Grant that she received in 2020. The institutional grant is awarded to Hollings, which then divides the funding among early-career researchers with promising proposals.
Guglietta has been investigating the role of the complement anaphylatoxin C3a receptor (C3aR). This receptor is part of the complement system, which, in turn, is part of the innate immune system. The complement system is made up of cell-bound and soluble proteins that react to kill foreign invaders like bacteria, remove dead or damaged cells and promote tissue regeneration.
C3a has potent antibacterial and antifungal properties. Together with its receptor, C3aR, it helps to maintain the delicate balance of microbiota within the gut and regulate immune responses. Removing or reducing the amount of C3aR can induce the growth of potentially harmful bacteria.
"If this protein is reduced, like we see in our system, what can happen is that you have a sudden increase in certain bacterial species that cause inflammation," Guglietta said. "This inflammation is not always bad in the sense that it can actually be important for the immune system to say, 'Hey, it is a tumor. Let's activate so that we can fight the cancer.'"
Guglietta's preclinical models show that in tumors in which C3aR has been reduced, immune cells come flooding in, and the tumor itself becomes vulnerable to immunotherapy.
"Now, our working hypothesis is that if we can block this protein and couple this treatment with immunotherapy, then we will make patients who would not normally respond to immunotherapy begin to respond and therefore make this cancer more curable for more people," Guglietta said.
Preclinical models showed that the approach worked with metastatic cancer as well as earlier-stage cancers.
Guglietta is collaborating with researchers at Johns Hopkins University and CellXAnalytics to build a reliable antibody for C3aR, which has been challenging because of the protein's structure.
However, she's hopeful that they'll have an antibody ready for testing in preclinical models before the end of the grant period. Ultimately, of course, the plan is to prepare for clinical trials in humans.
Guglietta said it has become increasingly clear that understanding the gut microbiome is critical to human health.
"What happens in the gut is crucial for controlling not only the diseases that occur in the gut but, really, the diseases that occur in the entire body," she said.
