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Key Points The evolution of cancer has been linked to shifts in the microbiome. It will be indispensable to identify individual strains and clones (rather than phyla and genera) that have optimal anticancer effects. For this, culturomics will be superior to deep-sequencing approaches. Therapeutic manipulation of the cancer-associated microbiome may be obtained by faecal microbiota transplantation, antibiotic treatment, prebiotics that favour the expansion of useful bacteria, dietary interventions or drugs that alter the composition of the gut flora. In preclinical models, defined strains of live microbial agents may be used to stimulate immunosurveillance against cancers, either alone or in combination with cancer therapeutics. Bacterial products that have potential antineoplastic or immunostimulatory properties include bacterial toxins, microbial ligands of pattern recognition receptors, as well as bacterial metabolites, including butyrate, polyamines and pyridoxine. Drugs that modify bacterial metabolism are being developed with the scope of inhibiting the production of carcinogenic products. The microbiota influences the development of cancer and the effect of cancer therapies. In this Review, the authors summarize the interactions between the microbiota, the immune system and tumours and how manipulation of the microbiota can be used therapeutically. The human gut microbiome modulates many host processes, including metabolism, inflammation, and immune and cellular responses. It is becoming increasingly apparent that the microbiome can also influence the development of cancer. In preclinical models, the host response to cancer treatment has been improved by modulating the gut microbiome; this is known to have an altered composition in many diseases, including cancer. In addition, cancer treatment with microbial agents or their products has the potential to shrink tumours. However, the microbiome could also negatively influence cancer prognosis through the production of potentially oncogenic toxins and metabolites by bacteria. Thus, future antineoplastic treatments could combine the modulation of the microbiome and its products with immunotherapeutics and more conventional approaches that directly target malignant cells.

Discoveries made in the past 5 years indicate that the composition of the intestinal microbiota has a major influence on the effectiveness of anticancer immunosurveillance and thereby contributes to the therapeutic activity of immune-checkpoint inhibitors that target cytotoxic T lymphocyte protein 4 (CTLA-4) or the programmed cell death protein 1 (PD-1)–programmed cell death 1 ligand 1 (PD-L1) axis, as well as the activity of immunogenic chemotherapies. Herein, we highlight some of the bacteria, such as Akkermansia muciniphila, Bacteroides fragilis, Bifidobacterium spp. and Faecalibacterium spp., that have been associated with favourable anticancer immune responses in both preclinical tumour models and patients with cancer. Importantly, these bacteria also seem to have a positive influence on general health, thus reducing the incidence of metabolic disorders and a wide range of chronic inflammatory pathologies. We surmise that a diverse and propitious microbial ecosystem favours organismal homeostasis, particularly at the level of the cancer–immune dialogue.

Key Points The cell-autonomous conception of cancer has been progressively substituted by a view in which interactions of malignant and stromal elements, including immune cells, condition the tumour microenvironment. Transplantable models of mouse cancers implanted in histocompatible, immunocompetent mice have spurred the development of immune checkpoint blockers, as well as the discovery that chemotherapy- and radiotherapy-induced immunogenic cell death stimulates therapeutically relevant anticancer immune responses. Carcinogen-induced models have been instrumental for the discovery of the major principles of anticancer immunoediting, including elimination, equilibrium and escape. Genetically engineered mouse models (GEMMs) are providing fundamental insights into tissue- and context-dependent mechanisms of immune recognition and suppression. Modern genome-editing technologies offer the possibility of exchanging individual mouse genes or entire loci with their human equivalents with the possibility of introducing human elements of the immune and haematological systems into a progressively 'humanized' environment. The combination of immunodeficiencies that affect the mouse immune system, the humanization of the mouse genome by knock in of human genes or loci and the transplantation of human immune cells and tumours provides ever more refined models for oncoimmunology. In this Review, Zitvogel et al . describe the mouse models of transplantable, carcinogen-induced and genetically engineered tumours that have laid the foundations of oncoimmunology. Fundamental cancer research and the development of efficacious antineoplastic treatments both rely on experimental systems in which the relationship between malignant cells and immune cells can be studied. Mouse models of transplantable, carcinogen-induced or genetically engineered malignancies — each with their specific advantages and difficulties — have laid the foundations of oncoimmunology. These models have guided the immunosurveillance theory that postulates that evasion from immune control is an essential feature of cancer, the concept that the long-term effects of conventional cancer treatments mostly rely on the reinstatement of anticancer immune responses and the preclinical development of immunotherapies, including currently approved immune checkpoint blockers. Specific aspects of pharmacological development, as well as attempts to personalize cancer treatments using patient-derived xenografts, require the development of mouse models in which murine genes and cells are replaced with their human equivalents. Such 'humanized' mouse models are being progressively refined to characterize the leukocyte subpopulations that belong to the innate and acquired arms of the immune system as they infiltrate human cancers that are subjected to experimental therapies. We surmise that the ever-advancing refinement of murine preclinical models will accelerate the pace of therapeutic optimization in patients.

Resident gut bacteria can affect patient responses to cancer immunotherapy (see the Perspective by Jobin). Routy et al. show that antibiotic consumption is associated with poor response to immunotherapeutic PD-1 blockade. They profiled samples from patients with lung and kidney cancers and found that nonresponding patients had low levels of the bacterium Akkermansia muciniphila . Oral supplementation of the bacteria to antibiotic-treated mice restored the response to immunotherapy. Matson et al. and Gopalakrishnan et al. studied melanoma patients receiving PD-1 blockade and found a greater abundance of “good” bacteria in the guts of responding patients. Nonresponders had an imbalance in gut flora composition, which correlated with impaired immune cell activity. Thus, maintaining healthy gut flora could help patients combat cancer. Science , this issue p. 91 , p. 104 , p. 97 ; see also p. 32 Gut bacteria influence patient response to cancer therapy. Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizable minority of cancer patients. We found that primary resistance to ICIs can be attributed to abnormal gut microbiome composition. Antibiotics inhibited the clinical benefit of ICIs in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICIs into germ-free or antibiotic-treated mice ameliorated the antitumor effects of PD-1 blockade, whereas FMT from nonresponding patients failed to do so. Metagenomics of patient stool samples at diagnosis revealed correlations between clinical responses to ICIs and the relative abundance of Akkermansia muciniphila . Oral supplementation with A. muciniphila after FMT with nonresponder feces restored the efficacy of PD-1 blockade in an interleukin-12–dependent manner by increasing the recruitment of CCR9 + CXCR3 + CD4 + T lymphocytes into mouse tumor beds.

Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis–specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA-4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade.

Cyclophosphamide is one of several clinically important cancer drugs whose therapeutic efficacy is due in part to their ability to stimulate antitumor immune responses. Studying mouse models, we demonstrate that cyclophosphamide alters the composition of microbiota in the small intestine and induces the translocation of selected species of Gram-positive bacteria into secondary lymphoid organs. There, these bacteria stimulate the generation of a specific subset of \"pathogenic\" T helper 17 (pT H 17) cells and memory T H 1 immune responses. Tumor-bearing mice that were germ-free or that had been treated with antibiotics to kill Gram-positive bacteria showed a reduction in pT H 17 responses, and their tumors were resistant to cyclophosphamide. Adoptive transfer of pT H 17 cells partially restored the antitumor efficacy of cyclophosphamide. These results suggest that the gut microbiota help shape the anticancer immune response.

Limited experimental evidence bridges nutrition and cancer immunosurveillance. Here, we show that ketogenic diet (KD) - or its principal ketone body, 3-hydroxybutyrate (3HB), most specifically in intermittent scheduling - induced T cell-dependent tumor growth retardation of aggressive tumor models. In conditions in which anti-PD-1 alone or in combination with anti-CTLA-4 failed to reduce tumor growth in mice receiving a standard diet, KD, or oral supplementation of 3HB reestablished therapeutic responses. Supplementation of KD with sucrose (which breaks ketogenesis, abolishing 3HB production) or with a pharmacological antagonist of the 3HB receptor GPR109A abolished the antitumor effects. Mechanistically, 3HB prevented the immune checkpoint blockade-linked upregulation of PD-L1 on myeloid cells, while favoring the expansion of CXCR3+ T cells. KD induced compositional changes of the gut microbiota, with distinct species such as Eisenbergiella massiliensis commonly emerging in mice and humans subjected to carbohydrate-low diet interventions and highly correlating with serum concentrations of 3HB. Altogether, these results demonstrate that KD induces a 3HB-mediated antineoplastic effect that relies on T cell-mediated cancer immunosurveillance.

The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (T FH ) cells and the efficacy of chemotherapy-induced immune responses. It remains unclear whether gut microbes contribute to the elicitation of T FH cell-driven responses. Here, we show that the ileal microbiota dictates tolerogenic versus immunogenic cell death of ileal intestinal epithelial cells (IECs) and the accumulation of T FH cells in patients with CC and mice. Suppression of IEC apoptosis led to compromised chemotherapy-induced immunosurveillance against CC in mice. Protective immune responses against CC were associated with residence of Bacteroides fragilis and Erysipelotrichaceae in the ileum. In the presence of these commensals, apoptotic ileal IECs elicited PD-1 + T FH cells in an interleukin-1R1- and interleukin-12-dependent manner. The ileal microbiome governed the efficacy of chemotherapy and PD-1 blockade in CC independently of microsatellite instability. These findings demonstrate that immunogenic ileal apoptosis contributes to the prognosis of chemotherapy-treated CC. Local microbiome composition influences treatment efficacy of chemotherapy in colon cancer via modulation of tolerogenic versus immunogenic ileal intestinal epithelial cell death, which in turn influences follicular helper T cell priming.

Melanoma prognosis is dictated by tumor-infiltrating lymphocytes, the migratory and functional behavior of which is guided by chemokine or cytokine gradients. Here, we retrospectively analyzed the expression patterns of 9 homing receptors (CCR/CXCR) in naive and memory CD4+ and CD8+ T lymphocytes in 57 patients with metastatic melanoma (MMel) with various sites of metastases to evaluate whether T cell CCR/CXCR expression correlates with intratumoral accumulation, metastatic progression, and/or overall survival (OS). Homing receptor expression on lymphocytes strongly correlated with MMel dissemination. Loss of CCR6 or CXCR3, but not cutaneous lymphocyte antigen (CLA), on circulating T cell subsets was associated with skin or lymph node metastases, loss of CXCR4, CXCR5, and CCR9 corresponded with lung involvement, and a rise in CCR10 or CD103 was associated with widespread dissemination. High frequencies of CD8+CCR9+ naive T cells correlated with prolonged OS, while neutralizing the CCR9/CCL25 axis in mice stimulated tumor progression. The expansion of CLA-expressing effector memory CD8+ T cells in response to a single administration of CTLA4 blockade predicted disease control at 3 months in 47 patients with MMel. Thus, specific CCR/CXCR expression patterns on circulating T lymphocytes may guide potential diagnostic and therapeutic approaches.

BackgroundProstate cancer (PC) responds to androgen deprivation therapy (ADT) usually in a transient fashion, progressing from hormone-sensitive PC (HSPC) to castration-resistant PC (CRPC). We investigated a mouse model of PC as well as specimens from PC patients to unravel an unsuspected contribution of thymus-derived T lymphocytes and the intestinal microbiota in the efficacy of ADT.MethodsPreclinical experiments were performed in PC-bearing mice, immunocompetent or immunodeficient. In parallel, we prospectively included 65 HSPC and CRPC patients (Oncobiotic trial) to analyze their feces and blood specimens.ResultsIn PC-bearing mice, ADT increased thymic cellularity and output. PC implanted in T lymphocyte-depleted or athymic mice responded less efficiently to ADT than in immunocompetent mice. Moreover, depletion of the intestinal microbiota by oral antibiotics reduced the efficacy of ADT. PC reduced the relative abundance of Akkermansia muciniphila in the gut, and this effect was reversed by ADT. Moreover, cohousing of PC-bearing mice with tumor-free mice or oral gavage with Akkermansia improved the efficacy of ADT. This appears to be applicable to PC patients because long-term ADT resulted in an increase of thymic output, as demonstrated by an increase in circulating recent thymic emigrant cells (sjTRECs). Moreover, as compared with HSPC controls, CRPC patients demonstrated a shift in their intestinal microbiota that significantly correlated with sjTRECs. While feces from healthy volunteers restored ADT efficacy, feces from PC patients failed to do so.ConclusionsThese findings suggest the potential clinical utility of reversing intestinal dysbiosis and repairing acquired immune defects in PC patients.