Two new studies in Science and Science Immunology spotlight a group of intestinal T cells with α4β7 integrin receptors that could be targeted to prevent resistance to immune checkpoint blockade (ICB) cancer immunotherapy. Both studies were conducted in mice and corroborated in samples from patients.
In the Science study, Marine Fidelle and colleagues evaluated how interactions between antibiotics, the gut microbiome, and α4β7+ CD4+ T cells promote immunosuppression within tumors and impair anti-PD-1 immunotherapy-induced immune activity. When they examined mice with fibrosarcomas that received broad-spectrum antibiotics, the researchers found that the intestines expressed far less of an adhesion molecule involved in lymphocyte homing called MAdCAM-1. Furthermore, two Enterocloster bacterial species came to dominate the gut microbiota. Notably, these species have also been observed in abundance in the stools of patients who are resistant to anti-PD-1 treatment. α4β7 receptors on RORγt+ regulatory T (Tr17) cells normally bind to MAdCAM-1 in the intestine, which retains Tr17 cells there and helps foster an anti-inflammatory gut environment. Fidelle et al. determined that Enterocloster metabolites drove MAdCAM-1 downregulation, which freed α4β7+ Tr17 cells to migrate to the tumors, where their immunosuppressive activity worked against PD-1 therapy. The team also showed that fecal transplants in mice prevented antibiotic-induced MAdCAM-1 deficiency, kept α4β7+ Tr17 cells localized to the gut, and reduced the development of immunotherapy resistance. The authors identified low serum soluble MAdCAM-1 as a potential marker of intestinal dysbiosis, and suggest that targeting MAdCAM-1-α4β7 interactions may be a means to improve anti-PD-1 immunotherapy outcomes.
By contrast, the Science Immunology study by Virginie Feliu and colleagues demonstrates how gut-resident α4β7+ T cells in certain contexts can actually enhance anticancer responses to metastatic tumors. Colorectal carcinomas were implanted into the livers of mice, a common site of extraintestinal metastasis. A subset of those mice also received an implant of colorectal carcinomas into the gut, representing the primary site for this cancer. They found that this second group of mice showed enhanced antimetastatic immunity and improved survival outcomes and determined that CD8+ cytotoxic T cells expressing α4β7 were a major element in this process. This antimetastatic effect was even more pronounced in the context of anti-PD-L1 treatment, which is notable given the fact that secondary liver tumors are often resistant to immunotherapy. Feliu et al. then assessed samples from 20 patients with stabilized metastatic colorectal cancer and saw that patient responsiveness to immunotherapy positively correlated with levels of α4β7+ CD8+ cytotoxic T cells circulating in the blood and no longer resident in the gut. "This unexpected extraintestinal role of gut T cells informs mechanisms of how antibiotics affect ICB responses, inspires therapeutic strategies to manipulate the [tumor microenvironment], and may yield new biomarkers to guide ICB use," write Brandon Pratt and J. Justin Milner in a related Perspective in Science.
Fidelle, M., et al. (2023) A microbiota-modulated checkpoint directs immunosuppressive intestinal T cells into cancers. Science. doi.org/10.1126/science.abo2296.