Newswise – WINSTON-SALEM, NC – July 29, 2022 – Researchers at the Wake Forest Institute for Regenerative Medicine (WFIRM) are using a tumor organoid system to examine the effects of metabolites secreted by bacteria on a specialized immunotherapy – point blockade immune control, a promising cancer treatment development – to determine why some patients do not respond or develop resistance to treatment over time.
According to Cancer.gov, immune checkpoints are a normal part of the immune system that engages when proteins on the surface of immune cells, called T cells, recognize and bind to partner proteins on other cells, including tumor cells. When this happens, an “off” signal is sent to the T cells and prevents the immune system from destroying the cancer cells. Immunotherapy drugs work to prevent the binding and “off” signal from being sent so that T cells can do their job and kill cancer cells.
Immune checkpoint blockade therapy has demonstrated good results in many types of cancer, including unresectable advanced or metastatic triple-negative breast cancer, and has recently been approved as a promising treatment. However, clinical data show that approximately 40% of breast cancer patients do not respond to treatment.
“Immune checkpoint blockade immunotherapy is one of the newest and most promising developments in cancer treatment,” said Konstantinos I. Votanopoulos, MD, PhD, professor of surgery at Atrium Health. Wake Forest Baptist Comprehensive Cancer Center and Director of Wake Forest Organoid Research. Center (WFORCE), a joint venture between WFIRM and the Cancer Center. “It can show profound effects in patients who respond; however, a large proportion of patients either show no response at all or develop resistance to treatment over time and we need to understand why.
By incorporating elements of the patient’s immune system into tumor organoids, “we can now study the unique and complex interactions between the tumor, the immune system and the microbiome,” Votanopoulos added.
The human microbiome and its role in cancer, and specifically how it affects response to therapies such as immunotherapy, is an emerging area of research interest. The human microbiome is made up of microbes – viruses, bacteria and fungi – that reside in the body and contribute to proper physiological functioning. It is often described as an invisible system within the human body that is affected by the genetics, geography, food, and lifestyle of the human host, and understanding by the scientific community is in its infancy.
In this study, recently published in Scientific Reports, the research team created a novel tumor organoid system that contains important components of the immune system to study microbiome-associated factors affecting the response to immune checkpoint blockade. The team was able to show that some of these bacteria-released factors (metabolites) enhanced immune cell viability and altered gene expression to prime the system for a more complete immune response, thereby increasing treatment efficacy.
Shay Soker, PhD, who leads the organoid research team at WFIRM and is co-director of WFORCE, said the findings validate the immune-enhancing tumor organoid system as a physiological duplicate representing the live state of the tumor microenvironment.
“A better understanding of the relationship between specific bacterial metabolites and the overall response to immune checkpoint blockade could be used to push for potential positive findings,” Soker said. “Procedures such as fecal transfer or dietary modification could also effectively induce a more therapy-friendly microbiome.”
Soker and Votanopoulos said more data is needed to determine the relationship between these receptors, bacterial metabolites, and therapeutic response. Further use of this model with patient-derived cells will help demonstrate the full effects of these factors, they added.
“These results suggest that further development of this model will eventually be an important clinical tool in the design and analysis of future trials for cancer treatments,” said Anthony Atala, MD, director of WFIRM. “Our goal is to integrate the immune-enhanced tumor organoid platform into the treatment decision-making process to better treat patients.”
Additional co-authors include: Ethan Shelkey, David Oommen, Elizabeth R. Stirling, David R. Soto-Pantoja, Katherine L Cook, and Yong Lu. The authors declare no competing interests.
This work was supported in part by a pilot award from the Breast Cancer Center of Excellence (DRS-P&SS NCI P30CA012197) and a pilot study fund from the Translational Science Center at Wake Forest University, Reynolda Campus. Shelkey is supported by the NIH-NIBIB T32 Training Program in Studies in Translational Regenerative Medicine (2T32EB014836). Stirling is supported by the NIH-NIAID T32 Training Program in Immunology and Pathogenesis (5T32AI007401).
About the Wake Forest Institute for Regenerative Medicine: The Wake Forest Institute for Regenerative Medicine is recognized as an international leader in translating scientific discoveries into clinical therapies, with many world firsts, including the development and implantation of the first modified organ in a patient. More than 400 people at the institute, the largest in the world, work on more than 40 different tissues and organs. A number of basic principles of tissue engineering and regenerative medicine were first developed at the institute. WFIRM researchers have successfully designed replacement tissues and organs in all four categories – flat structures, tubular tissues, hollow organs and solid organs – and 15 different applications of cell/tissue therapy technologies, such as skin, tissue Urethra, cartilage, bladders, muscles, kidneys, and vaginal organs have been used successfully in human patients. The institute, part of the Wake Forest School of Medicine, is located in the Innovation District in downtown Winston-Salem, North Carolina, and is driven by urgent patient needs. The institute is making a global difference in regenerative medicine through collaborations with more than 400 entities and institutions around the world, through its government, academic and industrial partnerships, its start-ups and through major initiatives in the technologies of advanced, such as tissue engineering, cell therapies. , diagnostics, drug discovery, biomanufacturing, nanotechnology, gene editing and 3D printing.