Wistar Scientists Find Gut Microbe Byproduct Drives Antitumor Immunity

The team identified the metabolite TMAO drives immune activation in the tumor microenvironment and boosts response to immune checkpoint blockade therapy in pancreatic cancer.

Rahul S. Shinde, D.V.M., Ph.D., Assistant Professor in the Immunology, Microenvironment, and Metastasis Program of Wistar’s Ellen and Ronald Caplan Cancer Center and the Institute’s inaugural Caspar Wistar Fellow published evidence in Science Immunology of a therapeutic target in the gut microbiome for pancreatic cancer.

Recently awarded the Pancreatic Cancer Action Network Career Development Award, Shinde focuses his research efforts on understanding the gut microbiome and identifying potential targets for cancer therapies. In this newly published paper, Shinde and his collaborators reveal that a metabolite derived from a gut microbe called trimethylamine N-oxide (abbreviated TMAO) boosts immunity against tumors by triggering immune activation in pancreatic cancer. Furthermore, the study provides evidence that targeting TMAO production in the gut microbiome could improve the efficacy of immune checkpoint blockade (ICB) therapy for the disease.

Pancreatic cancer is a particularly deadly disease with a tumor microenvironment that aggressively suppresses immune response. Immunotherapies can be improved by boosting immune activation in the tumor microenvironment – a function influenced by the gut microbiome. In the study, the researchers administered TMAO and observed effects on tumor growth and immune response in the tumor microenvironment. They found evidence that TMAO stimulated action from immune cells such as macrophages and T cells as well as increased pancreatic cancer’s responsiveness to ICB therapy, ultimately boosting the body’s ability to identify and attack cancer cells.

“With growing interest in selective targeting of the gut microbiome to improve cancer treatments, this study can create a new paradigm for discovering novel gut microbial metabolites influencing anti-tumor immunity and inform innovative treatment strategies for highly lethal and hard-to-treat pancreatic cancer,” says Shinde, corresponding author on the paper.

He elaborates that his findings raise a series of questions with clinical implications, including what sources of TMAO confer its anti-tumor effects and whether this beneficial TMAO can be achieved by altering these sources. Additionally, he emphasizes that potential future directions of this work could delve into understanding whether TMAO can promote anti-tumor immunity in other cancer types with treatment resistance.

Shinde collaborated with fellow Wistar principal investigators Chi Van Dang, M.D., Ph.D., Aaron Goldman Ph.D., Hsin-Yao Tang Ph.D., Noam Auslander, Ph.D., Mohamed Abdel-Mohsen, Ph.D., and Andrew Kossenkov, Ph.D. on this study.

This work was generously supported by the following: NIH, the W. W. Smith Charitable Trust, 2022 Pancreatic Cancer Action Network Career Development Award, Grant Number “22-20-SHIN,”, the Tobin-Kestenbaum families, as well as the Caspar Wistar Fellowship Program at The Wistar Institute.