RESUMEN
The gut microbiota influences the clinical responses of cancer patients to immunecheckpoint inhibitors (ICIs). However, there is no consensus definition of detrimental dysbiosis. Based on metagenomics (MG) sequencing of 245 non-small cell lung cancer (NSCLC) patient feces, we constructed species-level co-abundance networks that were clustered into species-interacting groups (SIGs) correlating with overall survival. Thirty-seven and forty-five MG species (MGSs) were associated with resistance (SIG1) and response (SIG2) to ICIs, respectively. When combined with the quantification of Akkermansia species, this procedure allowed a person-based calculation of a topological score (TOPOSCORE) that was validated in an additional 254 NSCLC patients and in 216 genitourinary cancer patients. Finally, this TOPOSCORE was translated into a 21-bacterial probe set-based qPCR scoring that was validated in a prospective cohort of NSCLC patients as well as in colorectal and melanoma patients. This approach could represent a dynamic diagnosis tool for intestinal dysbiosis to guide personalized microbiota-centered interventions.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Microbioma Gastrointestinal , Inmunoterapia , Neoplasias Pulmonares , Neoplasias , Femenino , Humanos , Masculino , Akkermansia , Carcinoma de Pulmón de Células no Pequeñas/microbiología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Disbiosis/microbiología , Heces/microbiología , Microbioma Gastrointestinal/efectos de los fármacos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Inmunoterapia/métodos , Neoplasias Pulmonares/microbiología , Neoplasias Pulmonares/tratamiento farmacológico , Metagenómica/métodos , Neoplasias/microbiología , Resultado del TratamientoRESUMEN
Inhibition of immune regulatory checkpoints, such as CTLA-4 and the PD-1-PD-L1 axis, is at the forefront of immunotherapy for cancers of various histological types. However, such immunotherapies fail to control neoplasia in a significant proportion of patients. Here, we review how a range of cancer-cell-autonomous cues, tumor-microenvironmental factors, and host-related influences might account for the heterogeneous responses and failures often encountered during therapies using immune-checkpoint blockade. Furthermore, we describe the emerging evidence of how the strong interrelationship between the immune system and the host microbiota can determine responses to cancer therapies, and we introduce a concept by which prior or concomitant modulation of the gut microbiome could optimize therapeutic outcomes upon immune-checkpoint blockade.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Receptores Coestimuladores e Inhibidores de Linfocitos T/inmunología , Resistencia a Antineoplásicos , Inmunoterapia/métodos , Neoplasias/terapia , Animales , Receptores Coestimuladores e Inhibidores de Linfocitos T/antagonistas & inhibidores , Humanos , Terapia Molecular Dirigida , Neoplasias/inmunología , Escape del Tumor , Microambiente TumoralRESUMEN
The efficacy of the anti-cancer immunomodulatory agent cyclophosphamide (CTX) relies on intestinal bacteria. How and which relevant bacterial species are involved in tumor immunosurveillance, and their mechanism of action are unclear. Here, we identified two bacterial species, Enterococcus hirae and Barnesiella intestinihominis that are involved during CTX therapy. Whereas E. hirae translocated from the small intestine to secondary lymphoid organs and increased the intratumoral CD8/Treg ratio, B. intestinihominis accumulated in the colon and promoted the infiltration of IFN-γ-producing γδT cells in cancer lesions. The immune sensor, NOD2, limited CTX-induced cancer immunosurveillance and the bioactivity of these microbes. Finally, E. hirae and B. intestinihominis specific-memory Th1 cell immune responses selectively predicted longer progression-free survival in advanced lung and ovarian cancer patients treated with chemo-immunotherapy. Altogether, E. hirae and B. intestinihominis represent valuable "oncomicrobiotics" ameliorating the efficacy of the most common alkylating immunomodulatory compound.
Asunto(s)
Ciclofosfamida/farmacología , Enterococcus hirae/inmunología , Factores Inmunológicos/inmunología , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Animales , Colon/inmunología , Colon/microbiología , Memoria Inmunológica/inmunología , Inmunoterapia/métodos , Interferón gamma/inmunología , Intestino Delgado/inmunología , Intestino Delgado/microbiología , Ratones , Ratones Endogámicos C57BL , Monitorización Inmunológica , Proteína Adaptadora de Señalización NOD2/inmunología , Células TH1/inmunologíaRESUMEN
Antibiotics (ABX) compromise the efficacy of programmed cell death protein 1 (PD-1) blockade in cancer patients, but the mechanisms underlying their immunosuppressive effects remain unknown. By inducing the down-regulation of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in the ileum, post-ABX gut recolonization by Enterocloster species drove the emigration of enterotropic α4ß7+CD4+ regulatory T 17 cells into the tumor. These deleterious ABX effects were mimicked by oral gavage of Enterocloster species, by genetic deficiency, or by antibody-mediated neutralization of MAdCAM-1 and its receptor, α4ß7 integrin. By contrast, fecal microbiota transplantation or interleukin-17A neutralization prevented ABX-induced immunosuppression. In independent lung, kidney, and bladder cancer patient cohorts, low serum levels of soluble MAdCAM-1 had a negative prognostic impact. Thus, the MAdCAM-1-α4ß7 axis constitutes an actionable gut immune checkpoint in cancer immunosurveillance.
Asunto(s)
Antibacterianos , Moléculas de Adhesión Celular , Resistencia a Antineoplásicos , Microbioma Gastrointestinal , Inhibidores de Puntos de Control Inmunológico , Tolerancia Inmunológica , Vigilancia Inmunológica , Integrinas , Mucoproteínas , Neoplasias , Animales , Humanos , Ratones , Antibacterianos/efectos adversos , Bacterias/inmunología , Moléculas de Adhesión Celular/metabolismo , Movimiento Celular , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Tolerancia Inmunológica/efectos de los fármacos , Integrinas/metabolismo , Interleucina-17/metabolismo , Mucoproteínas/metabolismo , Neoplasias/inmunología , Neoplasias/terapia , Células Th17/inmunología , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/microbiologíaRESUMEN
BACKGROUND: Prostate 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. METHODS: Preclinical 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. RESULTS: In 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. CONCLUSIONS: These findings suggest the potential clinical utility of reversing intestinal dysbiosis and repairing acquired immune defects in PC patients.
Asunto(s)
Microbioma Gastrointestinal , Neoplasias de la Próstata Resistentes a la Castración , Antagonistas de Andrógenos/farmacología , Antagonistas de Andrógenos/uso terapéutico , Andrógenos/uso terapéutico , Animales , Humanos , Sistema Inmunológico , Masculino , Ratones , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológicoRESUMEN
Aside from PD-L1 expression, biomarkers of response to immune checkpoint inhibitors (ICIs) in non-small-cell lung cancer (NSCLC) are needed. In a previous retrospective analysis, we documented that fecal Akkermansia muciniphila (Akk) was associated with clinical benefit of ICI in patients with NSCLC or kidney cancer. In the current study, we performed shotgun-metagenomics-based microbiome profiling in a large cohort of patients with advanced NSCLC (n = 338) treated with first- or second-line ICIs to prospectively validate the predictive value of fecal Akk. Baseline stool Akk was associated with increased objective response rates and overall survival in multivariate analyses, independent of PD-L1 expression, antibiotics, and performance status. Intestinal Akk was accompanied by a richer commensalism, including Eubacterium hallii and Bifidobacterium adolescentis, and a more inflamed tumor microenvironment in a subset of patients. However, antibiotic use (20% of cases) coincided with a relative dominance of Akk above 4.8% accompanied with the genus Clostridium, both associated with resistance to ICI. Our study shows significant differences in relative abundance of Akk that may represent potential biomarkers to refine patient stratification in future studies.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Akkermansia , Antígeno B7-H1 , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Receptor de Muerte Celular Programada 1 , Estudios Retrospectivos , Microambiente TumoralRESUMEN
Biomarkers guiding the neoadjuvant use of immune-checkpoint blockers (ICB) are needed for patients with localized muscle-invasive bladder cancers (MIBC). Profiling tumor and blood samples, we found that follicular helper CD4+ T cells (TFH) are among the best therapeutic targets of pembrolizumab correlating with progression-free survival. TFH were associated with tumoral CD8 and PD-L1 expression at baseline and the induction of tertiary lymphoid structures after pembrolizumab. Blood central memory TFH accumulated in tumors where they produce CXCL13, a chemokine found in the plasma of responders only. IgG4+CD38+ TFH residing in bladder tissues correlated with clinical benefit. Finally, TFH and IgG directed against urothelium-invasive Escherichia coli dictated clinical responses to pembrolizumab in three independent cohorts. The links between tumor infection and success of ICB immunomodulation should be prospectively assessed at a larger scale. SIGNIFICANCE: In patients with bladder cancer treated with neoadjuvant pembrolizumab, E. coli-specific CXCL13 producing TFH and IgG constitute biomarkers that predict clinical benefit. Beyond its role as a biomarker, such immune responses against E. coli might be harnessed for future therapeutic strategies. This article is highlighted in the In This Issue feature, p. 2221.
Asunto(s)
Neoplasias de la Vejiga Urinaria , Antígeno B7-H1 , Quimiocina CXCL13 , Escherichia coli , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoglobulina G , Músculos , Terapia Neoadyuvante , Receptor de Muerte Celular Programada 1 , Linfocitos T Colaboradores-Inductores , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
The cancer-immune dialogue subject to immuno-oncological intervention is profoundly influenced by microenvironmental factors. Indeed, the mucosal microbiota-and more specifically, the intestinal ecosystem-influences the tone of anticancer immune responses and the clinical benefit of immunotherapy. Antibiotics blunt the efficacy of immune checkpoint inhibitors (ICI), and fecal microbial transplantation may restore responsiveness of ICI-resistant melanoma. Here, we review the yin and yang of intestinal bacteria at the crossroads between the intestinal barrier, metabolism, and local or systemic immune responses during anticancer therapies. We discuss diagnostic tools to identify gut dysbiosis and the future prospects of microbiota-based therapeutic interventions. SIGNIFICANCE: Given the recent proof of concept of the potential efficacy of fecal microbial transplantation in patients with melanoma primarily resistant to PD-1 blockade, it is timely to discuss how and why antibiotics compromise the efficacy of cancer immunotherapy, describe the balance between beneficial and harmful microbial species in play during therapies, and introduce the potential for microbiota-centered interventions for the future of immuno-oncology.
Asunto(s)
Microbioma Gastrointestinal , Inmunoterapia/tendencias , Microbiota , Neoplasias , HumanosRESUMEN
The presence of Akkermansia muciniphila (Akk) in the human gut is associated with good health, leanness and fitness. Mouse experimentation has demonstrated positive effects for Akk, which counteracts aging, mediates antiobesity and antidiabetic effects, dampens inflammation and improves anticancer immunosurveillance. Clinical trials have confirmed antidiabetic effects for Akk. Here, we investigated the time-dependent effects of oral administration of Akk (which was live or pasteurized) and other bacteria to mice on the metabolome of the ileum, colon, liver and blood plasma. Metabolomics was performed by a combination of chromatographic and mass spectrometric methods, yielding a total of 1.637.227 measurements. Akk had major effects on metabolism, causing an increase in spermidine and other polyamines in the gut and in the liver. Pasteurized Akk (Akk-past) was more efficient than live Akk in elevating the intestinal concentrations of polyamines, short-chain fatty acids, 2-hydroxybutyrate, as well multiple bile acids, which also increased in the circulation. All these metabolites have previously been associated with human health, providing a biochemical basis for the beneficial effects of Akk.
Asunto(s)
Probióticos/farmacología , Administración Oral , Akkermansia , Animales , Ácidos Grasos Volátiles/metabolismo , Microbioma Gastrointestinal , Tracto Gastrointestinal/metabolismo , Hidroxibutiratos/metabolismo , Hígado/metabolismo , Metaboloma , Metabolómica , Ratones Endogámicos C57BL , Pasteurización , Poliaminas/metabolismo , Espermidina/metabolismoRESUMEN
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.
Asunto(s)
Dieta Cetogénica , Cuerpos Cetónicos/administración & dosificación , Neoplasias Experimentales/dietoterapia , Neoplasias Experimentales/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Ácido 3-Hidroxibutírico/administración & dosificación , Ácido 3-Hidroxibutírico/metabolismo , Animales , Antígeno CTLA-4/antagonistas & inhibidores , Línea Celular Tumoral , Terapia Combinada , Femenino , Microbioma Gastrointestinal/inmunología , Humanos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Cuerpos Cetónicos/metabolismo , Neoplasias Renales/dietoterapia , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/inmunología , Melanoma Experimental/dietoterapia , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Neoplasias Experimentales/inmunología , Receptores Acoplados a Proteínas G/antagonistas & inhibidoresRESUMEN
A deviated repertoire of the gut microbiome predicts resistance to cancer immunotherapy. Enterococcus hirae compensated cancer-associated dysbiosis in various tumor models. However, the mechanisms by which E. hirae restored the efficacy of cyclophosphamide administered with concomitant antibiotics remain ill defined. Here, we analyzed the multifaceted modes of action of this anticancer probiotic. Firstly, E. hirae elicited emigration of thymocytes and triggered systemic and intratumoral IFNγ-producing and CD137-expressing effector memory T cell responses. Secondly, E. hirae activated the autophagy machinery in enterocytes and mediated ATG4B-dependent anticancer effects, likely as a consequence of its ability to increase local delivery of polyamines. Thirdly, E. hirae shifted the host microbiome toward a Bifidobacteria-enriched ecosystem. In contrast to the live bacterium, its pasteurized cells or membrane vesicles were devoid of anticancer properties. These pleiotropic functions allow the design of optimal immunotherapies combining E. hirae with CD137 agonistic antibodies, spermidine, or Bifidobacterium animalis. We surmise that immunological, metabolic, epithelial, and microbial modes of action of the live E. hirae cooperate to circumvent primary resistance to therapy.
Asunto(s)
Antibacterianos/farmacología , Enterococcus hirae/inmunología , Neoplasias/tratamiento farmacológico , Probióticos/farmacología , Animales , Femenino , Microbioma Gastrointestinal/inmunología , Inmunoterapia/métodos , Células T de Memoria/inmunología , Ratones , Ratones Endogámicos C57BL , Neoplasias/inmunologíaRESUMEN
Accumulating evidence demonstrates the decisive role of the gut microbiota in determining the effectiveness of anticancer therapeutics such as immunogenic chemotherapy or immune checkpoint blockade in preclinical tumor models, as well as in cancer patients. In synthesis, it appears that a normal intestinal microbiota supports therapeutic anticancer responses, while a dysbiotic microbiota that lacks immunostimulatory bacteria or contains overabundant immunosuppressive species causes treatment failure. These findings have led to the design of clinical trials that evaluate the capacity of modulation of the gut microbiota to synergize with treatment and hence limit tumor progression. Along the lines of this Trial Watch, we discuss the rationale for harnessing the gut microbiome in support of cancer therapy and the progress of recent clinical trials testing this new therapeutic paradigm in cancer patients.
Asunto(s)
Microbioma Gastrointestinal , Neoplasias , Disbiosis , Humanos , Inmunoterapia , Neoplasias/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Accumulating evidence from preclinical studies and human trials demonstrated the crucial role of the gut microbiota in determining the effectiveness of anticancer therapeutics such as immunogenic chemotherapy or immune checkpoint blockade. In summary, it appears that a diverse intestinal microbiota supports therapeutic anticancer responses, while a dysbiotic microbiota composition that lacks immunostimulatory bacteria or contains overabundant immunosuppressive species causes treatment failure. In this review, we explore preclinical and translational studies highlighting how eubiotic and dysbiotic microbiota composition can affect progression-free survival in cancer patients.
Asunto(s)
Microbioma Gastrointestinal , Neoplasias , Disbiosis , Humanos , Inhibidores de Puntos de Control Inmunológico , Neoplasias/tratamiento farmacológico , SimbiosisRESUMEN
BACKGROUND: The development of immune checkpoint blockade (ICB) has revolutionized the clinical outcome of renal cell carcinoma (RCC). Nevertheless, improvement of durability and prediction of responses remain unmet medical needs. While it has been recognized that antibiotics (ATBs) decrease the clinical activity of ICB across various malignancies, little is known about the direct impact of distinct intestinal nonpathogenic bacteria (commensals) on therapeutic outcomes of ICB in RCC. OBJECTIVE: To evaluate the predictive value of stool bacteria composition for ICB efficacy in a cohort of advanced RCC patients. DESIGN, SETTING, AND PARTICIPANTS: We prospectively collected fecal samples from 69 advanced RCC patients treated with nivolumab and enrolled in the GETUG-AFU 26 NIVOREN microbiota translational substudy phase 2 trial (NCT03013335) at Gustave Roussy. We recorded patient characteristics including ATB use, prior systemic therapies, and response criteria. We analyzed 2994 samples of feces from healthy volunteers (HVs). In parallel, preclinical studies performed in RCC-bearing mice that received fecal transplant (FMT) from RCC patients resistant to ICB (NR-FMT) allowed us to draw a cause-effect relationship between gut bacteria composition and clinical outcomes for ICB. The influence of tyrosine kinase inhibitors (TKIs) taken before starting nivolumab on the microbiota composition has also been assessed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Metagenomic data (MG) from whole genome sequencing (WGS) were analyzed by multivariate and pairwise comparisons/fold ratio to identify bacterial fingerprints related to ATB or prior TKI exposure and patients' therapeutic response (overall response and progression-free survival), and compared with the data from cancer-free donors. RESULTS AND LIMITATIONS: Recent ATB use (nâ¯=â¯11; 16%) reduced objective response rates (from 28% to 9%, pâ¯<â¯0.03) and markedly affected the composition of the microbiota, facilitating the dominance of distinct species such as Clostridium hathewayi, which were also preferentially over-represented in stools from RCC patients compared with HVs. Importantly, TKIs taken prior to nivolumab had implications in shifting the microbiota composition. To establish a cause-effect relationship between gut bacteria composition and ICB efficacy, NR-FMT mice were successfully compensated with either FMT from responding RCC patients or beneficial commensals identified by WGS-MG (Akkermansia muciniphila and Bacteroides salyersiae). CONCLUSIONS: The composition of the microbiota is influenced by TKIs and ATBs, and impacts the success of immunotherapy. Future studies will help sharpen the role of these specific bacteria and their potential as new biomarkers. PATIENT SUMMARY: We used quantitative shotgun DNA sequencing of fecal microbes as well as preclinical models of fecal or bacterial transfer to study the association between stool composition and (pre)clinical outcome to immune checkpoint blockade. Novel insights into the pathophysiological relevance of intestinal dysbiosis in the prognosis of kidney cancer may lead to innovative therapeutic solutions, such as supplementation with probiotics to prevent primary resistance to therapy.
Asunto(s)
Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/microbiología , Resistencia a Antineoplásicos , Heces/microbiología , Microbioma Gastrointestinal , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/microbiología , Nivolumab/uso terapéutico , Animales , Humanos , Ratones , Valor Predictivo de las Pruebas , Estudios ProspectivosRESUMEN
The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (TFH) cells and the efficacy of chemotherapy-induced immune responses. It remains unclear whether gut microbes contribute to the elicitation of TFH 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 TFH 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+ TFH 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.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Microbioma Gastrointestinal/inmunología , Íleon/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Oxaliplatino/farmacología , Adenocarcinoma/inmunología , Adenocarcinoma/microbiología , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Antineoplásicos/uso terapéutico , Apoptosis/inmunología , Bacteroides fragilis , Línea Celular Tumoral , Neoplasias del Colon/inmunología , Neoplasias del Colon/microbiología , Neoplasias del Colon/patología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/inmunología , Células Epiteliales/patología , Femenino , Firmicutes , Microbioma Gastrointestinal/fisiología , Humanos , Íleon/inmunología , Íleon/microbiología , Íleon/patología , Muerte Celular Inmunogénica/efectos de los fármacos , Muerte Celular Inmunogénica/inmunología , Vigilancia Inmunológica/efectos de los fármacos , Vigilancia Inmunológica/inmunología , Interleucina-12/inmunología , Mucosa Intestinal , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Ratones , Persona de Mediana Edad , Oxaliplatino/uso terapéutico , Pronóstico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptores Tipo I de Interleucina-1/inmunología , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Linfocitos T Colaboradores-Inductores/inmunologíaRESUMEN
Intestinal microbiota have been proposed to induce commensal-specific memory T cells that cross-react with tumor-associated antigens. We identified major histocompatibility complex (MHC) class I-binding epitopes in the tail length tape measure protein (TMP) of a prophage found in the genome of the bacteriophage Enterococcus hirae Mice bearing E. hirae harboring this prophage mounted a TMP-specific H-2Kb-restricted CD8+ T lymphocyte response upon immunotherapy with cyclophosphamide or anti-PD-1 antibodies. Administration of bacterial strains engineered to express the TMP epitope improved immunotherapy in mice. In renal and lung cancer patients, the presence of the enterococcal prophage in stools and expression of a TMP-cross-reactive antigen by tumors correlated with long-term benefit of PD-1 blockade therapy. In melanoma patients, T cell clones recognizing naturally processed cancer antigens that are cross-reactive with microbial peptides were detected.
Asunto(s)
Antígenos de Neoplasias/inmunología , Bacteriófagos/inmunología , Enterococcus hirae/virología , Microbioma Gastrointestinal/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Inmunoterapia/métodos , Neoplasias/terapia , Proteínas de la Cola de los Virus/inmunología , Animales , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Alquilantes/uso terapéutico , Linfocitos T CD8-positivos/inmunología , Reacciones Cruzadas , Ciclofosfamida/uso terapéutico , Epítopos/inmunología , Heces/virología , Antígenos H-2/inmunología , Humanos , Ratones , Neoplasias/dietoterapia , Neoplasias/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Proteínas de la Cola de los Virus/uso terapéuticoRESUMEN
PD-1 blockade represents a major therapeutic avenue in anticancer immunotherapy. Delineating mechanisms of secondary resistance to this strategy is increasingly important. Here, we identified the deleterious role of signaling via the type I interferon (IFN) receptor in tumor and antigen presenting cells, that induced the expression of nitric oxide synthase 2 (NOS2), associated with intratumor accumulation of regulatory T cells (Treg) and myeloid cells and acquired resistance to anti-PD-1 monoclonal antibody (mAb). Sustained IFNß transcription was observed in resistant tumors, in turn inducing PD-L1 and NOS2 expression in both tumor and dendritic cells (DC). Whereas PD-L1 was not involved in secondary resistance to anti-PD-1 mAb, pharmacological or genetic inhibition of NOS2 maintained long-term control of tumors by PD-1 blockade, through reduction of Treg and DC activation. Resistance to immunotherapies, including anti-PD-1 mAb in melanoma patients, was also correlated with the induction of a type I IFN signature. Hence, the role of type I IFN in response to PD-1 blockade should be revisited as sustained type I IFN signaling may contribute to resistance to therapy.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Interferón Tipo I/metabolismo , Receptor de Muerte Celular Programada 1/inmunología , Transducción de Señal/efectos de los fármacos , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Antígeno B7-H1/metabolismo , Línea Celular Tumoral , Células Dendríticas/citología , Células Dendríticas/metabolismo , Resistencia a Antineoplásicos , Humanos , Estimación de Kaplan-Meier , Melanoma/tratamiento farmacológico , Melanoma/mortalidad , Melanoma/patología , Ratones , Ratones Endogámicos C57BL , Neoplasias/tratamiento farmacológico , Neoplasias/mortalidad , Neoplasias/patología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismoRESUMEN
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.
Asunto(s)
Microbioma Gastrointestinal/inmunología , Inmunidad Innata , Neoplasias/microbiología , Neoplasias/terapia , Antígeno B7-H1/inmunología , Antígeno B7-H1/uso terapéutico , Bacteroides fragilis/inmunología , Bacteroides fragilis/metabolismo , Bifidobacterium/inmunología , Bifidobacterium/metabolismo , Antígeno CTLA-4/inmunología , Antígeno CTLA-4/uso terapéutico , Faecalibacterium/inmunología , Faecalibacterium/metabolismo , Humanos , Monitorización Inmunológica , Neoplasias/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/uso terapéuticoRESUMEN
Accumulating evidence points to the impact of the gut microbiota in regulating various chronic inflammatory disorders such as cancers. The intestinal microbiome is not only influencing the spontaneous course of colon malignancies but also acts at distant sterile sites of neoplasia, mostly playing a detrimental role. By providing microbial-associated molecular patterns and potentially antigens sharing molecular mimicry with tumor antigens, our commensals modulate the local and the systemic immune tonus, eventually influencing tumor microenvironment. Complicating this algorithm, therapeutic interventions alter the delicate balance between the epithelium, the microbial community, and the intestinal immunity, governing the final clinical outcome. This seminar focused on the impact of the intestinal composition on the immunomodulatory and therapeutic activities of distinct compounds (alkylating agents, platinum salts and immunotherapies) used in oncology. This research opens up "the era of anticancer probiotics" aimed at restoring gut eubiosis for a better clinical outcome in cancer patients.
Asunto(s)
Microbioma Gastrointestinal/fisiología , Intestinos/microbiología , Neoplasias/terapia , Humanos , Neoplasias/microbiología , SimbiosisRESUMEN
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.