How microbiota improve immunotherapy

doi:10.1126/science.abl3656

GSTDTAP > 气候变化

DOI	10.1126/science.abl3656
	How microbiota improve immunotherapy
	Eduard Ansaldo; Yasmine Belkaid
	2021-08-27
发表期刊	Science
出版年	2021
英文摘要	Animals have coevolved with complex communities of microorganisms living on barrier tissues, referred to as the microbiota or commensals. The microbiota controls immune function not only locally within barrier tissues but also systemically, modulating functions such as hematopoiesis, immune system development, and responses to vaccines ([ 1 ][1]). The role of the microbiota in enhancing responses to cancer immunotherapy has represented a major focus of research ([ 2 ][2]–[ 7 ][3]), although the mechanisms have remained largely unclear. On page 1040 of this issue, Griffin et al. ([ 8 ][4]) show that members of the Enterococcus genus promote immunotherapy responses in mice through immunostimulatory muropeptides, which are structural units of bacterial cell walls. One of the most convincing pieces of evidence for the adjuvant role of the microbiota in immunotherapy came from recent clinical studies demonstrating that transplantation of fecal microbiota from melanoma patients responding to programmed cell death protein 1 (PD-1) immune checkpoint therapy, but not from nonresponders, improved the efficacy of these PD-1 inhibitors in melanoma patients who were previously refractory to therapy ([ 9 ][5], [ 10 ][6]). Because of the extraordinary diversity of the microbiota, identification of defined mechanisms represents an enormous challenge, and the causal microbes or pathways identified so far have differed ([ 3 ][7]–[ 7 ][3]). Griffin et al. focus on the genus Enterococcus , one of the taxa described to correlate with responses in patients treated with immune checkpoint therapy ([ 5 ][8], [ 6 ][9]). The authors identified multiple species within this genus that are able to promote responses to PD-1 ligand 1 (PD-L1) immunotherapy in mouse tumor models. Notably, immunotherapy-active enterococci included the common human commensal Enterococcus faecium , whereas other species such as E. faecalis provided no protection. The authors were guided by previous studies that characterized the distinct composition of E. faecium peptidoglycan, the major structural component in bacterial cell walls. Comparison of the structure of peptidoglycans across immunotherapy-active and -inactive enterococci revealed defined peptidoglycan patterns that correlated with increased response to immunotherapy. Using a comparative genomic analysis, Griffin et al. identified a cluster of peptidoglycan hydrolases conserved across immunotherapy-active species, including the peptidoglycan hydrolase secreted antigen A (SagA) that was sufficient to confer responses when ectopically expressed in E. faecalis . This was dependent on the innate immune sensor nucleotide-binding oligomerization domain–containing protein 2 (NOD2), which recognizes peptidoglycan-derived muropeptides. Of interest, NOD ligands have been associated with immune modulating effects of the microbiota, including hematopoiesis, response to vaccination, and susceptibility to Crohn’s disease ([ 11 ][10]–[ 13 ][11]). ![Figure][12] Microbiota enhance immunotherapy Microbiota can influence the response to cancer immunotherapy through multiple mechanisms. These include phage antigens that are cross-reactive with tumor cells, cell wall–derived muropeptides such as glutaminylmuramyl-dipeptide (GMDP), and commensal-derived inosine, all of which converge on increased type 1 immunity against the tumor in the context of immune checkpoint blockade therapy. GRAPHIC: V. ALTOUNIAN/ SCIENCE Griffin et al. take a critical step toward understanding the mechanism by which specific commensal species can promote responses to immunotherapy, but it is still unclear on which cell types NOD2 ligands are acting and how these lead to increased antitumor immunity. Although NOD1 is broadly expressed, NOD2 expression is restricted to immune cells and certain populations of nonhematopoietic cells such as intestinal epithelial cells ([ 13 ][11]). One possibility is that NOD2 ligands also act on myeloid cells in the tumor microenvironment and its draining lymph node to promote anticancer adaptive immunity. Of note, a recent study revealed that NOD2 ligand-based therapeutics modulated myelopoiesis in the bone marrow, leading to epigenetic rewiring of myeloid cells that were then able to overcome the immunosuppressive tumor microenvironment ([ 14 ][13]). Griffin et al. expand on a small number of studies that were able to provide a molecular link between a microbe and its antitumor effects in the context of immune checkpoint blockade ([ 7 ][3], [ 15 ][14]) (see the figure). A previous study identified commensal bacteria–derived inosine as a key determinant of Bifidobacterium pseudolongum and Akkermansia muciniphila to enhance the antitumor efficacy of immune checkpoint blockade through the promotion of type 1 immunity ([ 7 ][3]), a class of T cell–mediated immune responses associated with protective responses to pathogens. Similarly, Griffin et al. show that Enterococcus -derived peptidoglycan promotes the accumulation of cytotoxic CD8+ T cells and associated innate responses in the tumor microenvironment. A similar link between the microbiota and increased type 1 immunity has been observed in preclinical models and in responding patients in the context of cancer immunotherapy ([ 2 ][2]–[ 6 ][9]). Together, these observations argue that immunotherapy-adjuvant microbes may converge on type 1 immunity as a central effector mechanism, whereas the upstream pathways engaged by individual microbial taxa may be context and microbe dependent. Understanding the mechanism of action of the microbiota in improving responses to immune checkpoint therapy is key for our ability to therapeutically harness them for targeted adjuvant therapies. Optimal responses to immune checkpoint therapy are likely to involve numerous non–mutually exclusive and synergistic effects of the microbiota. For example, shared antigens between an Enterococcus bacteriophage and a tumor antigen have been shown to lead to commensal-specific T cells that are cross-reactive with tumor antigens after anti-PD1 treatment ([ 15 ][14]). Additionally, defined protective bacteria can also promote commensal-specific adaptive immune responses in the context of immunotherapy ([ 3 ][7], [ 6 ][9]). Whether these commensal-specific responses play an active role in the antitumor effects or whether they are simply a by-product of the immunostimulatory activity of these bacteria remains to be determined. Finally, translocation of commensals to the tumor bed, which can be enhanced owing to barrier disruption caused by immunotherapy, has also been proposed as a potential antitumor mechanism ([ 2 ][2]). The study of Griffin et al. opens an avenue to harness endogenous adjuvants to fight cancer by designing targeted therapeutics that recapitulate the effects of the microbiota. This study also further illustrates the need to move away from “needle-in-the-haystack” single microbes as causal agents toward the identification of druggable canonical pathways and molecular determinants. 1. [↵][15]1. E. Ansaldo, 2. T. K. Farley, 3. Y. Belkaid , Annu. Rev. Immunol. 39, 449 (2021). [OpenUrl][16] 2. [↵][17]1. G. D. Sepich-Poore et al ., Science 371, eabc4552 (2021). 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领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/336641
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Eduard Ansaldo,Yasmine Belkaid. How microbiota improve immunotherapy[J]. Science,2021.
APA	Eduard Ansaldo,&Yasmine Belkaid.(2021).How microbiota improve immunotherapy.Science.
MLA	Eduard Ansaldo,et al."How microbiota improve immunotherapy".Science (2021).