Hollings immunologist receives NCI grant to fuel colon cancer development studies

Finding clues to what may be spurring the development of colon cancer, MUSC Hollings Cancer Center cancer immunologist Silvia Guglietta, Ph.D., will explore how a protein called complement component 3a receptor (C3aR) might be instrumental in controlling colon cancer development and response to therapy by altering a person’s immune responses, gut microbiome and intestinal barrier functions.

Guglietta recently received a five-year research project grant (R01) from the National Cancer Institute, which provides $2.4 million to further her studies in colon cancer inflammation.

Cancer in the large intestine, colon cancer, is the second leading cause of cancer death. There has been an alarming rise in colon cancer among younger individuals. According to the Colon Cancer Coalition, colorectal cancer (cancer of the colon or rectum) may be the leading cause of cancer death in adults under 50 by 2030.

Even worse are the trends in younger adults, one reason she’s passionate about this research. “Colon cancer may be more invasive and lead to a worse prognosis in younger individuals. My research focuses on understanding changes in the colon immune environment that may lead to cancer development. The goal is to learn to identify the early events that may predispose a person to colon cancer development so we can develop more effective ways to intervene and prevent cancer growth,” said Guglietta, an assistant professor in the Department of Regenerative Medicine and Cell Biology at the Medical University of South Carolina.

Guglietta’s passion for investigating challenging cancer problems grew from her personal experience. Before joining MUSC in 2018, she received her Ph.D. from the University of Rome and postdoctoral training at the European Institute of Oncology in Milan, Italy. Her mother’s stage 4 lung cancer diagnosis in 2008 diverted Guglietta’s research focus from the immune responses in hepatitis C virus-infected patients to cancer immunology.

“Watching my mom go through painful chemotherapy treatments that overall did not help was very frustrating. Back then, there were no immunotherapy options,” said Guglietta. Since that life-changing experience, she has built her research program by making key observations in the patient population and then turning to her research models to understand the critical biology that drives human cancer.

The project that led to the grant funding began when Guglietta discovered a reduction of C3aR in colon cancer patients compared with healthy people. The C3aR protein is a part of the innate immune system, which is responsible for delivering a rapid response after being triggered by nonspecific signals from bacteria, viruses and environmental factors. The other half of the immune system, adaptive immunity, delivers a more complex and targeted attack against foreign pathogens.

“The difference in C3aR levels in colon cancer patients versus healthy patients was striking, so I turned to our mouse model of intestinal cancer, which has a mutation that is present in 90% of human colon cancer,” said Guglietta. Typically, these mice develop small intestine tumors and no colon tumors. However, removing the C3aR protein from the mice led to modifications of the gut microbiota, which is the large community of microorganisms inhabiting our gut, and development of colon cancer. Guglietta said that this model more closely resembles the human development of colon cancer.

 

Using this new mouse model, Guglietta and collaborator Carsten Krieg, Ph.D., dissected the tumor immune environment of the colon tumors that formed in the mice after C3aR was removed. Krieg is a pioneer of mass cytometry at MUSC – an advanced analysis technique that lets researchers measure over 40 parameters on a single cell.

The researchers found that the tumors from their mouse model of colon cancer had both innate and adaptive immune responses. Guglietta said that this is very rare in colon cancer. Since the absence of C3aR correlated with the inflammatory immune response, they hypothesized that the absence of C3aR may cause low-level inflammation that supports colon cancer development. This finding will potentially lead to new therapeutic avenues in this cancer model and hopefully in patients.

“We know from several immunotherapy clinical trials that many colon cancers do not have immune cells in them, which is a major barrier for treating patients with immunotherapy. Our early results show that the absence or reduction of C3aR may increase the number of certain immune cells in colon tumors,” said Guglietta, explaining how her future research seeks to understand the immune system’s intricate role in colon cancer promotion and prevention. While chronic, or long-term inflammation, may lead to colon cancer development, tumors with immune cell activity tend to respond better to anti-cancer immunotherapy treatments.

The R01 grant will also support the researcher’s investigation into colon cancer disparities. With the help of Hollings researcher and epidemiologist Kristin Wallace, Ph.D., Guglietta is collecting colon cancer samples from African American and Caucasian patients to determine if there are any racial differences in the expression of the C3aR protein. Early results suggest differences in several innate immune components, but that needs to be studied further to see if C3aR may be one of the biological factors that can explain the disparity in colon cancer development and prognosis between African Americans and Caucasians.

Guglietta said that support from Hollings, colleagues and her mentor and collaborator, Stephen Tomlinson, Ph.D., an expert in the complement system, has been critical to the success of this project thus far. “Both the American Cancer Society Institutional Research Grant and Center of Biomedical Research Excellence (COBRE) in Digestive and Liver Disease funding, which I received through Hollings and MUSC, helped me achieve this goal and perform all of the initial experiments that went into the grant application.”

Receiving this grant was very rewarding, she said. “The NCI was very supportive of the grant, especially since the role of complement in cancer is still underexplored. As a result of this grant, I have been invited to present at the NCI workshop, “Animal Models for Cancer Interception and Precision Prevention,” and talk about my mouse models for advancing our understanding of early-stage cancer development,” said Guglietta, adding that the workshop will be held on October 13 and 14.

Since Guglietta’s early data shows that a downregulation, or reduction, of C3aR may predispose people to “silent inflammation” that fuels the development of future cancer, many avenues may be explored. The effect of the C3aR protein may also be applied to other cancers, especially those that arise at mucosal surfaces, which form a barrier between the outside environment and our body, since those areas are more sensitive to inflammation, Guglietta said.

“I suspect that multiple lifestyle factors, such as highly processed diets, may affect the expression of C3aR, ultimately causing a status of latent inflammation and immune changes that over time promote cancer development. I look forward to being able to use the grant funds and my research models to help provide answers for both clinicians and patients,” said Guglietta.

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