Following up on our previous post from the CRI-CIMT-EATI-AACR Second International Cancer Immunotherapy Conference in New York City, which covered the tumor microenvironment, we now turn to the another important factor in cancer immunology: the different populations of bacteria that inhabit our bodies, mostly in our guts, and are referred to collectively as the microbiota.
Dan Littman, M.D., Ph.D., a professor at the New York University School of Medicine and a member of CRI’s Scientific Advisory Council, is one of the world’s foremost experts on how these bacteria interact with and influence the immune system, and Tuesday night he received the 2016 William B. Coley for his many contributions to this area of research. Littman opened day two of CICON16 with the Coley Lecture and described how these bacteria are necessary for the development of certain immune cells, such as Th17 cells.
Depending on where in the gut they are encountered, these bacteria can stimulate different types of responses, which, if not properly regulated, can cause inflammation nearby. Furthermore, even though the bacteria remain in the gut, they can induce systemic effects. In pregnant mice for example, Littman showed that Th17 cell-mediated inflammation is linked to neurodevelopmental, autism-like disorders in their offspring.
Later, Giorgio Trinchieri, M.D., who is director of the National Cancer Institute’s Cancer and Inflammation Program, and a member of CRI’s Scientific Advisory Council, discussed the role of the microbiota in cancer, and showed that some gut bacteria can cause inflammation that promotes the development and progression of colorectal cancer (CRC). Surprisingly, transferring pro-cancer microbes from mice with CRC tumors into healthy mice was enough to induce CRC formation in them, too. However, Dr. Trinchieri also stressed that bacteria aren’t all bad for us, and some can even help protect us from cancer.
The next speaker, Laurence Zitvogel, M.D., Ph.D., the director of the Tumour Immunology and Immunotherapy group at the Institut Gustave Roussy in France, expanded on these beneficial functions. For example, the bacterium E. hirae (EH) can increase the ratio of anti-cancer T cells to pro-cancer regulatory T cells and Th17 cells, and appears to promote anti-cancer activity in patients.
In lung and ovarian cancer patients who were treated with the chemotherapy drug cyclophosphamide, tumors took longer to progress in those who had memory T cells against EH. While the patients weren’t cured, this temporary delay could provide a window of opportunity during which immune-focused treatments could be administered and help patients permanently turn the tide in their favor. This also suggests ways we could boost the immune systems of patients without this pre-existing immunity to improve their survival.
In addition to chemotherapy, bacteria can also improve immunotherapy responses. Zitvogel showed that, for CTLA-4 blockade therapy to work against CRC, sarcoma, and melanoma in mice, gut bacteria are required. This demonstrates the far-reaching impact bacteria of the gut can have in cancer immunotherapy, including for cancers outside the gut. Furthermore, exposing T cells to bacteria before transferring them into bacteria-free mice enables the mice to respond to anti-CTLA-4 treatment. Perhaps most surprising of all, transplanting stool samples from melanoma patients into bacteria-free mice also enabled them to benefit from anti-CTLA-4 immunotherapy.
Finally, Jason Hudak, Ph.D., a CRI-funded postdoctoral fellow at Harvard Medical School, shared his efforts to improve our understanding of the behavior of these gut bacteria. Hudak developed a way to label certain nutrients that are used by bacteria, and this allows him to follow them in real-time as these nutrients are incorporated into bacterial molecules and then eventually taken up by immune cells. This valuable new tool should enable scientists to better characterize the roles of gut bacteria and shed light on their interactions with the immune system in the context of colorectal cancer. This will hopefully lead to insights that guide improved treatment approaches as well as provide doctors with enhanced diagnostic capabilities, so they can detect the signs of CRC at earlier stages of its development.