Microbiota-driven antitumour immunity mediated by dendritic cell migration
Yi-Tzu Lin, Shota Fukuoka, Shohei Koyama, Daisuke Motooka, Dieter M. Tourlousse, Yuko Shigeno, Yuki Matsumoto, Hiroyuki Yamano, Kazutoshi Murotomi, Hideyuki Tamaki, Takuma Irie, Eri Sugiyama, Shogo Kumagai, Kota Itahashi, Tokiyoshi Tanegashima, Kaori Fujimaki, Sachiko Ito, Mariko Shindo, Takahiro Tsuji, Hiroaki Wake, Keisuke Watanabe, Yuka Maeda, Tomohiro Enokida, Makoto Tahara, Riu Yamashita, Takao Fujisawa, Motoo Nomura, Akihito Kawazoe, Kōichi Goto, Toshihiko Doi, Kohei Shitara, Hiroyuki Mano, Yuji Sekiguchi, Shota Nakamura, Yoshimi Benno, Hiroyoshi Nishikawa
Abstract
Gut microbiota influence the antitumour efficacy of immune checkpoint blockade1–6, but the mechanisms of action have not been fully elucidated. Here, we show that a new strain of the bacterial genus Hominenteromicrobium (designated YB328) isolated from the faeces of patients who responded to programmed cell death 1 (PD-1) blockade augmented antitumour responses in mice. YB328 activated tumour-specific CD8+ T cells through the stimulation of CD103+CD11b− conventional dendritic cells (cDCs), which, following exposure in the gut, migrated to the tumour microenvironment. Mice showed improved antitumour efficacy of PD-1 blockade when treated with faecal transplants from non-responder patients supplemented with YB238. This result suggests that YB328 could function in a dominant manner. YB328-activated CD103+CD11b− cDCs showed prolonged engagement with tumour-specific CD8+ T cells and promoted PD-1 expression in these cells. Moreover, YB238-augmented antitumour efficacy of PD-1 blockade treatment was observed in multiple mouse models of cancer. Patients with elevated YB328 abundance had increased infiltration of CD103+CD11b− cDCs in tumours and had a favourable response to PD-1 blockade therapy in various cancer types. We propose that gut microbiota enhance antitumour immunity by accelerating the maturation and migration of CD103+CD11b− cDCs to increase the number of CD8+ T cells that respond to diverse tumour antigens. A newly identified bacterial strain (YB328) isolated from the faeces of patients who responded to immune checkpoint blockade therapies can promote antitumour immunity through the activation of tumour-specific CD8+ T cells.