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Summary: Advances in survival analysis have facilitated unprecedented flexibility in data modeling, yet there remains a lack of tools for illustrating the influence of continuous covariates on predicted survival outcomes. We propose the utilization of a colored contour plot to depict the predicted survival probabilities over time. Our approach is capable of supporting conventional models, including the Cox and Fine-Gray models. However, its capability shines when coupled with cutting-edge machine learning models such as random survival forests and deep neural networks. Availability and implementation: We provide a Shiny app at https://biostatistics.mdanderson.org/shinyapps/survivalContour/ and an R package available at https://github.com/YushuShi/survivalContour as implementations of this tool.
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Adenoid cystic carcinoma (ACC) is a rare, usually slow-growing yet aggressive head and neck malignancy. Despite its clinical significance, our understanding of the cellular evolution and microenvironment in ACC remains limited. We investigated the intratumoral microbiomes of 50 ACC tumor tissues and 33 adjacent normal tissues using 16S rRNA gene sequencing. This allowed us to characterize the bacterial communities within the ACC and explore potential associations between the bacterial community structure, patient clinical characteristics, and tumor molecular features obtained through RNA sequencing. The bacterial composition in the ACC was significantly different from that in adjacent normal salivary tissue, and the ACC exhibited diverse levels of species richness. We identified two main microbial subtypes within the ACC: oral-like and gut-like. Oral-like microbiomes, characterized by increased diversity and abundance of Neisseria, Leptotrichia, Actinomyces, Streptococcus, Rothia, and Veillonella (commonly found in healthy oral cavities), were associated with a less aggressive ACC-II molecular subtype and improved patient outcomes. Notably, we identified the same oral genera in oral cancer and head and neck squamous cell carcinomas. In both cancers, they were part of shared oral communities associated with a more diverse microbiome, less aggressive tumor phenotype, and better survival that reveal the genera as potential pancancer biomarkers for favorable microbiomes in ACC and other head and neck cancers. Conversely, gut-like intratumoral microbiomes, which feature low diversity and colonization by gut mucus layer-degrading species, such as Bacteroides, Akkermansia, Blautia, Bifidobacterium, and Enterococcus, were associated with poorer outcomes. Elevated levels of Bacteroides thetaiotaomicron were independently associated with significantly worse survival and positively correlated with tumor cell biosynthesis of glycan-based cell membrane components.
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Carcinoma Adenoide Cístico , Neoplasias de Cabeça e Pescoço , Microbiota , RNA Ribossômico 16S , Humanos , Carcinoma Adenoide Cístico/microbiologia , Carcinoma Adenoide Cístico/patologia , Neoplasias de Cabeça e Pescoço/microbiologia , Neoplasias de Cabeça e Pescoço/patologia , Feminino , Masculino , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética , Idoso , Adulto , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificaçãoRESUMO
The human gut microbiome plays a vital role in preserving individual health and is intricately involved in essential functions. Imbalances or dysbiosis within the microbiome can significantly impact human health and are associated with many diseases. Several metaproteomics platforms are currently available to study microbial proteins within complex microbial communities. In this study, we attempted to develop an integrated pipeline to provide deeper insights into both the taxonomic and functional aspects of the cultivated human gut microbiomes derived from clinical colon biopsies. We combined a rapid peptide search by MSFragger against the Unified Human Gastrointestinal Protein database and the taxonomic and functional analyses with Unipept Desktop and MetaLab-MAG. Across seven samples, we identified and matched nearly 36,000 unique peptides to approximately 300 species and 11 phyla. Unipept Desktop provided gene ontology, InterPro entries, and enzyme commission number annotations, facilitating the identification of relevant metabolic pathways. MetaLab-MAG contributed functional annotations through Clusters of Orthologous Genes and Non-supervised Orthologous Groups categories. These results unveiled functional similarities and differences among the samples. This integrated pipeline holds the potential to provide deeper insights into the taxonomy and functions of the human gut microbiome for interrogating the intricate connections between microbiome balance and diseases.
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Hematologic side effects are associated with prolonged antibiotic exposure in up to 34% of patients. Neutropenia, reported in 10-15% of patients, increases the risk of sepsis and death. Murine studies have established a link between the intestinal microbiota and normal hematopoiesis. We sought to identify predisposing factors, presence of microbiota-derived metabolites, and changes in intestinal microbiota composition in otherwise healthy pediatric patients who developed neutropenia after prolonged courses of antibiotics. In this multi-center study, patients with infections requiring anticipated antibiotic treatment of two or more weeks were enrolled. Stool samples were obtained at the start and completion of antibiotics and at the time of neutropenia. We identified 10 patients who developed neutropenia on antibiotics and 29 controls matched for age, sex, race, and ethnicity. Clinical data demonstrated no association between neutropenia and type of infection or type of antibiotic used; however intensive care unit admission and length of therapy were associated with neutropenia. Reduced intestinal microbiome richness and decreased abundance of Lachnospiraceae family members correlated with neutropenia. Untargeted stool metabolomic profiling revealed several metabolites that were depleted exclusively in patients with neutropenia, including members of the urea cycle pathway, pyrimidine metabolism and fatty acid metabolism that are known to be produced by Lachnospiraceae . Our study confirms a relationship between intestinal microbiota disruption and abnormal hematopoiesis and identifies taxa and metabolites likely to contribute to microbiota-sustained hematopoiesis. As the microbiome is a key determinant of stem cell transplant and immunotherapy outcomes, these findings are likely to be of broad significance. Key Points: Neutropenia occurred in 17% of patients receiving prolonged antibiotic therapy.We found no association between neutropenia and type of infection or class of antibiotic used. Development of neutropenia after prolonged antibiotic treatment was associated with decreased prevalence of Lachnospiraceae and Lachnospiraceae metabolites such as citrulline.
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MOTIVATION: Although the human microbiome plays a key role in health and disease, the biological mechanisms underlying the interaction between the microbiome and its host are incompletely understood. Integration with other molecular profiling data offers an opportunity to characterize the role of the microbiome and elucidate therapeutic targets. However, this remains challenging to the high dimensionality, compositionality, and rare features found in microbiome profiling data. These challenges necessitate the use of methods that can achieve structured sparsity in learning cross-platform association patterns. RESULTS: We propose Tree-Aggregated factor RegressiOn (TARO) for the integration of microbiome and metabolomic data. We leverage information on the taxonomic tree structure to flexibly aggregate rare features. We demonstrate through simulation studies that TARO accurately recovers a low-rank coefficient matrix and identifies relevant features. We applied TARO to microbiome and metabolomic profiles gathered from subjects being screened for colorectal cancer to understand how gut microrganisms shape intestinal metabolite abundances. AVAILABILITY AND IMPLEMENTATION: The R package TARO implementing the proposed methods is available online at https://github.com/amishra-stats/taro-package.
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Microbiota , Humanos , Software , Metabolômica/métodos , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/metabolismo , Microbioma Gastrointestinal , AlgoritmosRESUMO
An enzyme that remodels the cell wall of Enterococcus faecium helps these gut bacteria to divide and generate peptide fragments that enhance the immune response against cancer.
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ABSTRACT: Disruption of the intestinal microbiome is observed with acute graft-versus-host disease (GVHD) of the lower gastrointestinal (LGI) tract, and fecal microbiota transplantation (FMT) has successfully cured steroid-refractory cases. In this open-label, single-arm, pilot study, third-party, single-donor FMT was administered in combination with systemic corticosteroids to participants with high-risk acute LGI GVHD, with a focus on treatment-naïve cases. Participants were scheduled to receive 1 induction dose (15 capsules per day for 2 consecutive days), followed by 3 weekly maintenance doses, consisting of 15 capsules per dose. The primary end point of the study was feasibility, which would be achieved if ≥80% of participants able to swallow ≥40 of the 75 scheduled capsules. Ten participants (9 treatment-naïve; 1 steroid-refractory) were enrolled and treated. The study met the primary end point, with 9 of 10 participants completing all eligible doses. Organ-specific LGI complete response rate at day 28 was 70%. Initial clinical response was observed within 1 week for all responders, and clinical responses were durable without recurrent LGI GVHD in complete responders. Exploratory analyses suggest that alpha diversity increased after FMT. Although recipient microbiome composition never achieved a high degree of donor similarity, expansion of donor-derived species and increases in tryptophan metabolites and short-chain fatty acids were observed within the first 7 days after FMT. Investigation into the use of microbiome-targeted interventions earlier in the treatment paradigm for acute LGI GVHD is warranted. This trial was registered at www.ClinicalTrials.gov as #NCT04139577.
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Transplante de Microbiota Fecal , Doença Enxerto-Hospedeiro , Humanos , Doença Enxerto-Hospedeiro/terapia , Doença Enxerto-Hospedeiro/etiologia , Transplante de Microbiota Fecal/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Microbioma Gastrointestinal , Idoso , Projetos Piloto , Doença Aguda , Resultado do TratamentoRESUMO
Tools for genome-wide rapid identification of peptide-major histocompatibility complex targets of T-cell receptors (TCR) are not yet universally available. We present a new antigen screening method, the T-synapse (Tsyn) reporter system, which includes antigen-presenting cells (APC) with a Fas-inducible NF-κB reporter and T cells with a nuclear factor of activated T cells (NFAT) reporter. To functionally screen for target antigens from a cDNA library, productively interacting T cell-APC aggregates were detected by dual-reporter activity and enriched by flow sorting followed by antigen identification quantified by deep sequencing (Tsyn-seq). When applied to a previously characterized TCR specific for the E7 antigen derived from human papillomavirus type 16 (HPV16), Tsyn-seq successfully enriched the correct cognate antigen from a cDNA library derived from an HPV16-positive cervical cancer cell line. Tsyn-seq provides a method for rapidly identifying antigens recognized by TCRs of interest from a tumor cDNA library. See related Spotlight by Makani and Joglekar, p. 515.
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Sinapses Imunológicas , Receptores de Antígenos de Linfócitos T , Linfócitos T , Humanos , Células Apresentadoras de Antígenos/imunologia , Linhagem Celular Tumoral , Biblioteca Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 16/genética , Sinapses Imunológicas/imunologia , Fatores de Transcrição NFATC/metabolismo , Fatores de Transcrição NFATC/imunologia , Proteínas E7 de Papillomavirus/imunologia , Proteínas E7 de Papillomavirus/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/imunologiaRESUMO
Immune checkpoint inhibitors (ICIs) have transformed the treatment paradigm for many cancer types. The clinical use of ICIs is increasing rapidly, including in combinations associated with increased risk of toxicities, termed "immune-related adverse events" (irAEs). Therefore, MD Anderson Cancer Center (MDACC) in Houston, Texas has proactively responded by developing a priority endeavor known as the Immuno-Oncology Toxicity (IOTOX) initiative. This strategic initiative aims to facilitate the seamless integration of key domains: (1) standardized clinical practice and innovative decision toolsets; (2) patient and provider education; and (3) a comprehensive clinical and translational research platform. The ultimate goal of this initiative is to develop and disseminate clinical best practices and biologic insights into irAEs to improve outcomes of patients with irAEs at MDACC and in the wider oncology community.
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Inibidores de Checkpoint Imunológico , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/terapia , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/terapia , Texas , Imunoterapia/métodos , Imunoterapia/efeitos adversosRESUMO
BACKGROUND: This study investigated the influence of oral microbial features on the trajectory of oral mucositis (OM) in patients with squamous cell carcinoma of the head and neck. METHODS: OM severity was assessed and buccal swabs were collected at baseline, at the initiation of cancer treatment, weekly during cancer treatment, at the termination of cancer treatment, and after cancer treatment termination. The oral microbiome was characterized via the 16S ribosomal RNA V4 region with the Illumina platform. Latent class mixed-model analysis was used to group individuals with similar trajectories of OM severity. Locally estimated scatterplot smoothing was used to fit an average trend within each group and to assess the association between the longitudinal OM scores and longitudinal microbial abundances. RESULTS: Four latent groups (LGs) with differing patterns of OM severity were identified for 142 subjects. LG1 has an early onset of high OM scores. LGs 2 and 3 begin with relatively low OM scores until the eighth and 11th week, respectively. LG4 has generally flat OM scores. These LGs did not vary by treatment or clinical or demographic variables. Correlation analysis showed that the abundances of Bacteroidota, Proteobacteria, Bacteroidia, Gammaproteobacteria, Enterobacterales, Bacteroidales, Aerococcaceae, Prevotellaceae, Abiotrophia, and Prevotella_7 were positively correlated with OM severity across the four LGs. Negative correlation was observed with OM severity for a few microbial features: Abiotrophia and Aerococcaceae for LGs 2 and 3; Gammaproteobacteria and Proteobacteria for LGs 2, 3, and 4; and Enterobacterales for LGs 2 and 4. CONCLUSIONS: These findings suggest the potential to personalize treatment for OM. PLAIN LANGUAGE SUMMARY: Oral mucositis (OM) is a common and debilitating after effect for patients treated for squamous cell carcinoma of the head and neck. Trends in the abundance of specific microbial features may be associated with patterns of OM severity over time. Our findings suggest the potential to personalize treatment plans for OM via tailored microbiome interventions.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Microbiota , Estomatite , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Carcinoma de Células Escamosas/tratamento farmacológicoRESUMO
Motivation: Although the human microbiome plays a key role in health and disease, the biological mechanisms underlying the interaction between the microbiome and its host are incompletely understood. Integration with other molecular profiling data offers an opportunity to characterize the role of the microbiome and elucidate therapeutic targets. However, this remains challenging to the high dimensionality, compositionality, and rare features found in microbiome profiling data. These challenges necessitate the use of methods that can achieve structured sparsity in learning cross-platform association patterns. Results: We propose Tree-Aggregated factor RegressiOn (TARO) for the integration of microbiome and metabolomic data. We leverage information on the phylogenetic tree structure to flexibly aggregate rare features. We demonstrate through simulation studies that TARO accurately recovers a low-rank coefficient matrix and identifies relevant features. We applied TARO to microbiome and metabolomic profiles gathered from subjects being screened for colorectal cancer to understand how gut microrganisms shape intestinal metabolite abundances. Availability and implementation: The R package TARO implementing the proposed methods is available online at https://github.com/amishra-stats/taro-package .
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Manipulation of the gut microbiome using live biotherapeutic products shows promise for clinical applications but remains challenging to achieve. Here, we induced dysbiosis in 56 healthy volunteers using antibiotics to test a synbiotic comprising the infant gut microbe, Bifidobacterium longum subspecies infantis (B. infantis), and human milk oligosaccharides (HMOs). B. infantis engrafted in 76% of subjects in an HMO-dependent manner, reaching a relative abundance of up to 81%. Changes in microbiome composition and gut metabolites reflect altered recovery of engrafted subjects compared with controls. Engraftment associates with increases in lactate-consuming Veillonella, faster acetate recovery, and changes in indolelactate and p-cresol sulfate, metabolites that impact host inflammatory status. Furthermore, Veillonella co-cultured in vitro and in vivo with B. infantis and HMO converts lactate produced by B. infantis to propionate, an important mediator of host physiology. These results suggest that the synbiotic reproducibly and predictably modulates recovery of a dysbiotic microbiome.
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Microbioma Gastrointestinal , Microbiota , Simbióticos , Lactente , Humanos , Adulto , Disbiose , Leite Humano , Ácido Láctico , VeillonellaRESUMO
Jarosch et al.1 have deeply characterized immune cell infiltrates in gastrointestinal (GI) biopsies from individuals with GI graft-versus-host disease (GI-GvHD) using single-cell RNA sequencing and ChipCytometry. Individuals with severe GI-GvHD demonstrated increased clonally expanded cytotoxic CD8 T cells in GI biopsies.
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Gastroenteropatias , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Gastroenteropatias/etiologia , Gastroenteropatias/patologia , Biópsia , Doença Enxerto-Hospedeiro/patologiaRESUMO
T cells are the central drivers of many inflammatory diseases, but the repertoire of tissue-resident T cells at sites of pathology in human organs remains poorly understood. We examined the site-specificity of T cell receptor (TCR) repertoires across tissues (5 to 18 tissues per patient) in prospectively collected autopsies of patients with and without graft-versus-host disease (GVHD), a potentially lethal tissue-targeting complication of allogeneic hematopoietic cell transplantation, and in mouse models of GVHD. Anatomic similarity between tissues was a key determinant of TCR repertoire composition within patients, independent of disease or transplant status. The T cells recovered from peripheral blood and spleens in patients and mice captured a limited portion of the TCR repertoire detected in tissues. Whereas few T cell clones were shared across patients, motif-based clustering revealed shared repertoire signatures across patients in a tissue-specific fashion. T cells at disease sites had a tissue-resident phenotype and were of donor origin based on single-cell chimerism analysis. These data demonstrate the complex composition of T cell populations that persist in human tissues at the end stage of an inflammatory disorder after lymphocyte-directed therapy. These findings also underscore the importance of studying T cell in tissues rather than blood for tissue-based pathologies and suggest the tissue-specific nature of both the endogenous and posttransplant T cell landscape.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Camundongos , Animais , Linfócitos T/patologia , Doença Enxerto-Hospedeiro/patologia , Receptores de Antígenos de Linfócitos TRESUMO
Respiratory inflammation in bronchiolitis obliterans syndrome (BOS) after hematopoietic cell transplantation (HCT) is poorly understood. Clinical criteria for early-stage BOS (stage 0p) often capture HCT recipients without BOS. Measuring respiratory tract inflammation may help identify BOS, particularly early BOS. We conducted a prospective observational study in HCT recipients with new-onset BOS (n = 14), BOS stage 0p (n = 10), and recipients without lung impairment with (n = 3) or without (n = 8) chronic graft-versus-host disease and measured nasal inflammation using nasosorption at enrollment and then every 3 mo for 1 y. We divided BOS stage 0p into impairment that did not return to baseline values (preBOS, n = 6), or transient impairment (n = 4). We tested eluted nasal mucosal lining fluid from nasosorption matrices for inflammatory chemokines and cytokines using multiplex magnetic bead immunoassays. We analyzed between-group differences using the Kruskal-Wallis method, adjusting for multiple comparisons. We found increased nasal inflammation in preBOS and therefore directly compared patients with preBOS to those with transient impairment, as this would be of greatest diagnostic relevance. After adjusting for multiple corrections, we found significant increases in growth factors (FGF2, TGF-α, GM-CSF, VEGF), macrophage activation (CCL4, TNF-α, IL-6), neutrophil activation (CXCL2, IL-8), T cell activation (CD40 ligand, IL-2, IL-12p70, IL-15), type 2 inflammation (eotaxin, IL-4, IL-13), type 17 inflammation (IL-17A), dendritic maturation (FLT3 ligand, IL-7), and counterregulatory molecules (PD-L1, IL-1 receptor antagonist, IL-10) in preBOS patients compared to transient impairment. These differences waned over time. In conclusion, a transient multifaceted nasal inflammatory response is associated with preBOS. Our findings require validation in larger longitudinal cohorts.
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Síndrome de Bronquiolite Obliterante , Bronquiolite Obliterante , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Transplante de Pulmão , Humanos , Citocinas , Bronquiolite Obliterante/diagnóstico , Bronquiolite Obliterante/etiologia , Bronquiolite Obliterante/metabolismo , Pulmão/metabolismo , Doença Enxerto-Hospedeiro/diagnóstico , Inflamação , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
Immune checkpoint inhibitors (ICIs) target advanced malignancies with high efficacy but also predispose patients to immune-related adverse events like immune-mediated colitis (IMC). Given the association between gut bacteria with response to ICI therapy and subsequent IMC, fecal microbiota transplantation (FMT) represents a feasible way to manipulate microbial composition in patients, with a potential benefit for IMC. Here, we present a large case series of 12 patients with refractory IMC who underwent FMT from healthy donors as salvage therapy. All 12 patients had grade 3 or 4 ICI-related diarrhea or colitis that failed to respond to standard first-line (corticosteroids) and second-line immunosuppression (infliximab or vedolizumab). Ten patients (83%) achieved symptom improvement after FMT, and three patients (25%) required repeat FMT, two of whom had no subsequent response. At the end of the study, 92% achieved IMC clinical remission. 16S rRNA sequencing of patient stool samples revealed that compositional differences between FMT donors and patients with IMC before FMT were associated with a complete response after FMT. Comparison of pre- and post-FMT stool samples in patients with complete responses showed significant increases in alpha diversity and increases in the abundances of Collinsella and Bifidobacterium, which were depleted in FMT responders before FMT. Histologically evaluable complete response patients also had decreases in select immune cells , including CD8+ T cells, in the colon after FMT when compared with non-complete response patients (n = 4). This study validates FMT as an effective treatment strategy for IMC and gives insights into the microbial signatures that may play a critical role in FMT response.
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Colite , Transplante de Microbiota Fecal , Inibidores de Checkpoint Imunológico , Inibidores de Checkpoint Imunológico/efeitos adversos , Colite/induzido quimicamente , Colite/terapia , Transplante de Microbiota Fecal/métodos , RNA Ribossômico 16S/genética , Fezes/microbiologia , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , IdosoRESUMO
Bloodstream infections (BSIs) pose a significant mortality risk for acute myeloid leukemia (AML) patients. It has been previously reported that intestinal domination (>30% relative abundance [RA] attributed to a single taxon) with the infecting taxa often precedes BSI in stem cell transplant patients. Using 16S rRNA amplicon sequencing, we analyzed oral and stool samples from 63 AML patients with BSIs to determine the correlation between the infectious agent and microbiome composition. Whole-genome sequencing and antimicrobial susceptibilities were performed on all BSI isolates. Species-level detection of the infectious agent and presence of antibiotic resistance determinants in the stool (blaCTX-M-15, blaCTX-M-14, cfrA, and vanA) were confirmed via digital droplet PCR (ddPCR). Individuals with Escherichia coli (stool P < 0.001), Pseudomonas aeruginosa (oral P = 0.004, stool P < 0.001), and viridans group streptococci (VGS) (oral P = 0.001) bacteremia had a significantly higher relative abundance of those respective genera than other BSI patients, which appeared to be site specific. Although 78% of patients showed presence of the infectious genera in the stool and/or saliva, only 7 exhibited microbiome domination. ddPCR confirmed species specificity of the 16S data and detected the antibiotic resistance determinants found in the BSI isolates within concurrent stools. Although gastrointestinal (GI) domination by an infecting organism was not present at the time of most BSIs in AML, the pathogens, along with AMR elements, were detectable in the majority of patients. Thus, rapid genetic assessment of oral and stool samples for the presence of potential pathogens and AMR determinants might inform personalized therapeutic approaches in immunocompromised patients with suspected infection. IMPORTANCE A major cause of mortality in hematologic malignancy patients is BSI. Previous studies have demonstrated that bacterial translocation from the GI microbiome is a major source of BSIs and is often preceded by increased levels of the infectious taxa in the GI (>30% abundance by 16S rRNA sequencing). In this study, we sought to better understand how domination and abundance levels of the oral and gut microbiome relate to bacteremia occurrence in acute myeloid leukemia patients. We conclude that analyses of both oral and stool samples can help identify BSI and antimicrobial resistance determinants, thus potentially improving the timing and tailoring of antibiotic treatment strategies for high-risk patients.
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Bacteriemia , Microbioma Gastrointestinal , Leucemia Mieloide Aguda , Microbiota , Humanos , Microbioma Gastrointestinal/genética , RNA Ribossômico 16S/genética , Bacteriemia/microbiologia , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/tratamento farmacológico , Antibacterianos/farmacologia , Antibacterianos/uso terapêuticoRESUMO
Increasing evidence suggests that the gut microbiome may modulate the efficacy of cancer immunotherapy. In a B cell lymphoma patient cohort from five centers in Germany and the United States (Germany, n = 66; United States, n = 106; total, n = 172), we demonstrate that wide-spectrum antibiotics treatment ('high-risk antibiotics') prior to CD19-targeted chimeric antigen receptor (CAR)-T cell therapy is associated with adverse outcomes, but this effect is likely to be confounded by an increased pretreatment tumor burden and systemic inflammation in patients pretreated with high-risk antibiotics. To resolve this confounding effect and gain insights into antibiotics-masked microbiome signals impacting CAR-T efficacy, we focused on the high-risk antibiotics non-exposed patient population. Indeed, in these patients, significant correlations were noted between pre-CAR-T infusion Bifidobacterium longum and microbiome-encoded peptidoglycan biosynthesis, and CAR-T treatment-associated 6-month survival or lymphoma progression. Furthermore, predictive pre-CAR-T treatment microbiome-based machine learning algorithms trained on the high-risk antibiotics non-exposed German cohort and validated by the respective US cohort robustly segregated long-term responders from non-responders. Bacteroides, Ruminococcus, Eubacterium and Akkermansia were most important in determining CAR-T responsiveness, with Akkermansia also being associated with pre-infusion peripheral T cell levels in these patients. Collectively, we identify conserved microbiome features across clinical and geographical variations, which may enable cross-cohort microbiome-based predictions of outcomes in CAR-T cell immunotherapy.
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Microbioma Gastrointestinal , Linfoma de Células B , Receptores de Antígenos Quiméricos , Humanos , Microbioma Gastrointestinal/genética , Imunoterapia , Imunoterapia Adotiva/efeitos adversos , Linfócitos T , Antígenos CD19RESUMO
ABSTRACT: Allogeneic hematopoietic cell transplantation (alloHCT) is a standard curative therapy for a variety of benign and malignant hematological diseases. Previously, patients who underwent alloHCT were at high risk for complications with potentially life-threatening toxicities, including a variety of opportunistic infections as well as acute and chronic manifestations of graft-versus-host disease (GVHD), where the transplanted immune system can produce inflammatory damage to the patient. With recent advances, including newer conditioning regimens, advances in viral and fungal infection prophylaxis, and novel GVHD prophylactic and treatment strategies, improvements in clinical outcomes have steadily improved. One modality with great potential that has yet to be fully realized is targeting the microbiome to further improve clinical outcomes.In recent years, the intestinal microbiota, which includes bacteria, fungi, viruses, and other microbes that reside within the intestinal tract, has become established as a potent modulator of alloHCT outcomes. The composition of intestinal bacteria, in particular, has been found in large multicenter prospective studies to be strongly associated with GVHD, treatment-related mortality, and overall survival. Murine studies have demonstrated a causal relationship between intestinal microbiota injury and aggravated GVHD, and more recently, clinical interventional studies of repleting the intestinal microbiota with fecal microbiota transplantation have emerged as effective therapies for GVHD. How the composition of the intestinal bacterial microbiota, which is often highly variable in alloHCT patients, can modulate GVHD and other outcomes is not fully understood. Recent studies, however, have begun to make substantial headway, including identifying particular bacterial subsets and/or bacterial-derived metabolites that can mediate harm or benefit. Here, the authors review recent studies that have improved our mechanistic understanding of the relationship between the microbiota and alloHCT outcomes, as well as studies that are beginning to establish strategies to modulate the microbiota with the hope of optimizing clinical outcomes.