According to researchers in their new study published in Cell, probiotic bacteria travel from the gut and establish in melanoma tumors, where they directly stimulate immune cells to make cancer immunotherapy more effective.
The study showed that Lactobacillus reuteri stimulates cancer-killing T cells by secreting a compound called indole-3-aldehyde, or I3A. When the researchers gave mice a diet rich in the amino acid tryptophan—which the bacteria convert to I3A—immunotherapy drugs had a stronger effect on restraining tumor size and prolonging survival. The findings lay the groundwork for clinical trials to test whether I3A treatments or combining probiotics and diet could improve outcomes in melanoma patients undergoing immunotherapy.
"We knew that gut microbes influence immunotherapy response, but there were still big questions about how they do this and whether they act from the gut or if they have to be at the tumor site," said senior author Marlies Meisel, PhD, assistant professor in the Department of Immunology at Pitt's School of Medicine and member of the Cancer Immunology and Immunotherapy Program (CIIP) at UPMC Hillman Cancer Center. "Our study is the first to show that orally administered bacteria increase efficacy of cancer immunotherapy by moving to tumors outside of the gut where they directly impact immune cells in the tumor."
The gut microbiome is an important factor in why immunotherapy—which helps the body's immune system recognize and kill cancer cells—is effective for some patients but not others. Several recent studies have also found a link between probiotic supplements and immunotherapy response in melanoma patients.
To learn more, Meisel and her colleagues fed L. reuteri, a bacterium that is often part of commercially available probiotics, to germ-free mice with melanoma. They showed that the bacteria moved from the gut to tumors, where they established and persisted over time. Compared to control mice that did not receive bacteria, those given L. reuteri had greater quantities of more potent CD8, or "killer," T cells at the tumor site, the tumors shrank more, and the mice lived longer.
And the effects of L. reuteri weren't limited to melanoma. In mouse models of adenocarcinoma, fibrosarcoma and breast cancer, the bacterium similarly moved to tumors beyond the gut and suppressed cancer growth.
Delving deeper, the researchers showed that L. reuteri stimulates immunity in tumors by producing I3A, which activates a receptor in CD8 cells. Although the receptor is found in almost every cell in the body, I3A acts specifically on CD8 cells to enhance their cancer-killing abilities. When the researchers removed the receptor within these cells, the bacteria no longer induced anti-tumor immunity, showing that the effect is dependent on this receptor in CD8 T cells. Using a genetically modified strain of L. reuteri that can't produce I3A, they demonstrated that this compound is essential for the bacterium's effect on enhancing anti-tumor immunity and tumor suppression.
"While the microbiome of tumors beyond the gut, including melanoma, had been described, the concept that tumor microbes play an active role in mediating cancer immunotherapy efficacy had not been demonstrated," said Meisel. "So, we were surprised to find that I3A released by L. reuteri within the tumor enhanced immunotherapy response whereas the presence of L. reuteri in the gut was insufficient to have an anti-tumor effect."
While retailers cannot make any claims about probiotics and any form of cancer, this study represents how powerful some strains can be in helping promote targeted immune response.
References:
Bender MJ, et al. “Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment.” Cell, 2023; DOI: 10.1016/j.cell.2023.03.011
Feature
According to researchers in their new study published in Cell, probiotic bacteria travel from the gut and establish in melanoma tumors, where they directly stimulate immune cells to make cancer immunotherapy more effective.
The study showed that Lactobacillus reuteri stimulates cancer-killing T cells by secreting a compound called indole-3-aldehyde, or I3A. When the researchers gave mice a diet rich in the amino acid tryptophan—which the bacteria convert to I3A—immunotherapy drugs had a stronger effect on restraining tumor size and prolonging survival. The findings lay the groundwork for clinical trials to test whether I3A treatments or combining probiotics and diet could improve outcomes in melanoma patients undergoing immunotherapy.
"We knew that gut microbes influence immunotherapy response, but there were still big questions about how they do this and whether they act from the gut or if they have to be at the tumor site," said senior author Marlies Meisel, PhD, assistant professor in the Department of Immunology at Pitt's School of Medicine and member of the Cancer Immunology and Immunotherapy Program (CIIP) at UPMC Hillman Cancer Center. "Our study is the first to show that orally administered bacteria increase efficacy of cancer immunotherapy by moving to tumors outside of the gut where they directly impact immune cells in the tumor."
The gut microbiome is an important factor in why immunotherapy—which helps the body's immune system recognize and kill cancer cells—is effective for some patients but not others. Several recent studies have also found a link between probiotic supplements and immunotherapy response in melanoma patients.
To learn more, Meisel and her colleagues fed L. reuteri, a bacterium that is often part of commercially available probiotics, to germ-free mice with melanoma. They showed that the bacteria moved from the gut to tumors, where they established and persisted over time. Compared to control mice that did not receive bacteria, those given L. reuteri had greater quantities of more potent CD8, or "killer," T cells at the tumor site, the tumors shrank more, and the mice lived longer.
And the effects of L. reuteri weren't limited to melanoma. In mouse models of adenocarcinoma, fibrosarcoma and breast cancer, the bacterium similarly moved to tumors beyond the gut and suppressed cancer growth.
Delving deeper, the researchers showed that L. reuteri stimulates immunity in tumors by producing I3A, which activates a receptor in CD8 cells. Although the receptor is found in almost every cell in the body, I3A acts specifically on CD8 cells to enhance their cancer-killing abilities. When the researchers removed the receptor within these cells, the bacteria no longer induced anti-tumor immunity, showing that the effect is dependent on this receptor in CD8 T cells. Using a genetically modified strain of L. reuteri that can't produce I3A, they demonstrated that this compound is essential for the bacterium's effect on enhancing anti-tumor immunity and tumor suppression.
"While the microbiome of tumors beyond the gut, including melanoma, had been described, the concept that tumor microbes play an active role in mediating cancer immunotherapy efficacy had not been demonstrated," said Meisel. "So, we were surprised to find that I3A released by L. reuteri within the tumor enhanced immunotherapy response whereas the presence of L. reuteri in the gut was insufficient to have an anti-tumor effect."
While retailers cannot make any claims about probiotics and any form of cancer, this study represents how powerful some strains can be in helping promote targeted immune response.
References:
Bender MJ, et al. “Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment.” Cell, 2023; DOI: 10.1016/j.cell.2023.03.011
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