Tumor Microbiome Research Articles

Recent progress in nanomaterials for bacteria-related tumor therapy.

Many studies suggest that tumor microbiome closely relates to the oncogenesis and anti-tumor responses in multiple cancer types (e.g., colorectal cancer (CRC), breast cancer, lung cancer and pancreatic cancer), thereby raising an emerging research area of bacteria-related tumor therapy. Nanomaterials have long been used for both cancer and bacterial infection treatment, holding great potential for bacteria-related tumor therapy. In this review, we summarized recent progress in nanomaterials for bacteria-related tumor therapy. We focus on the types and mechanisms of pathogenic bacteria in the development and promotion of cancers and emphasize how nanomaterials work. We also briefly discuss the design principles and challenges of nanomaterials for bacteria-related tumor therapy. We hope this review can provide some insights into this emerging and rapidly growing research area.

Exploring the impact of non-small cell lung cancer tumor microbiome on the efficacy of chemotherapy and immune checkpoint inhibitors

Exploring the impact of non-small cell lung cancer tumor microbiome on the efficacy of chemotherapy and immune checkpoint inhibitors

Predictable regulation of survival by intratumoral microbe-immune crosstalk in patients with lung adenocarcinoma.

Intratumoral microbiota can regulate the tumor immune microenvironment (TIME) and mediate tumor prognosis by promoting inflammatory response or inhibiting anti-tumor effects. Recent studies have elucidated the potential role of local tumor microbiota in the development and progression of lung adenocarcinoma (LUAD). However, whether intratumoral microbes are involved in the TIME that mediates the prognosis of LUAD remains unknown. Here, we obtained the matched tumor microbiome and host transcriptome and survival data of 478 patients with LUAD in The Cancer Genome Atlas (TCGA). Machine learning models based on immune cell marker genes can predict 1- to 5-year survival with relative accuracy. Patients were stratified into high- and low-survival-risk groups based on immune cell marker genes, with significant differences in intratumoral microbial communities. Specifically, patients in the high-risk group had significantly higher alpha diversity (p < 0.05) and were characterized by an enrichment of lung cancer-related genera such as Streptococcus. However, network analysis highlighted a more active pattern of dominant bacteria and immune cell crosstalk in TIME in the low-risk group compared to the high-risk group. Our study demonstrated that intratumoral microbiota-immune crosstalk was strongly associated with prognosis in LUAD patients, which would provide new targets for the development of precise therapeutic strategies.

Microbiome in Cancer Development and Treatment.

Targeting the microbiome, microbiota-derived metabolites, and related pathways represents a significant challenge in oncology. Microbiome analyses have confirmed the negative impact of cancer treatment on gut homeostasis, resulting in acute dysbiosis and severe complications, including massive inflammatory immune response, mucosal barrier disruption, and bacterial translocation across the gut epithelium. Moreover, recent studies revealed the relationship between an imbalance in the gut microbiome and treatment-related toxicity. In this review, we provide current insights into the role of the microbiome in tumor development and the impact of gut and tumor microbiomes on chemo- and immunotherapy efficacy, as well as treatment-induced late effects, including cognitive impairment and cardiotoxicity. As discussed, microbiota modulation via probiotic supplementation and fecal microbiota transplantation represents a new trend in cancer patient care, aiming to increase bacterial diversity, alleviate acute and long-term treatment-induced toxicity, and improve the response to various treatment modalities. However, a more detailed understanding of the complex relationship between the microbiome and host can significantly contribute to integrating a microbiome-based approach into clinical practice. Determination of causal correlations might lead to the identification of clinically relevant diagnostic and prognostic microbial biomarkers. Notably, restoration of intestinal homeostasis could contribute to optimizing treatment efficacy and improving cancer patient outcomes.

The tumoral microbiome of pancreatic intraductal papillary mucinous neoplasm: A single-center retrospective cohort study.

Pancreatic intraductal papillary mucinous neoplasm (IPMN) is one of the most common precancerous lesions of pancreatic carcinoma. Studies have found that the tumoral microbiome has an important influence on pancreatic carcinoma. However, the tumoral microbiome of IPMNs has rarely been explored. Tumoral microbiome gene sequencing was carried out using 16 specimens of IPMN and 45 specimens of IPMN with associated invasive carcinoma (IPMN-IC) by 2bRAD sequencing for microbiome. The profile of the tumoral microbiome was summarized. Associations of the tumoral microbiome with disease grade, histological subtype, and prognosis were analyzed. A total of 598 species of microbes were identified, comprising 228 genera, 109 families, 60 orders, 29 classes, 14 phyla, and 2 kingdoms. The genus Pseudomonas was detected more frequently and had higher relative abundance in IPMN-ICs; Alcaligenes faecalis was detected with higher relative abundance in IPMNs. Bifidobacterium pseudolongum had a higher relative abundance in the IPMN-IC group, regardless of histological subtype. Moreover, among patients with IPMN-ICs, those with a high relative abundance of B.pseudolongum had better overall survival than those with a low relative abundance. Patients who were positive for Staphylococcus aureus or Mycolicibacillus koreensis had shorter survival. The presence of S.aureus was an independent risk factor for poor prognosis. There are enriching tumoral microbes in IPMN. The tumoral microbiome of IPMN is different from that of IPMN-IC.

Exogenous Sequences in Tumors and Immune Cells (Exotic): A Tool for Estimating the Microbe Abundances in Tumor RNA-seq Data.

The intrinsic tumor microbiome holds great potential for its ability to predict various aspects of cancer biology and as a target for rational manipulation. Here, we describe a tool to quantify microbes from within tumor RNA-seq and apply it to two independent datasets. We show new associations with clinical variables that justify biomarker uses and more experimentation into the mechanisms by which tumor microbiomes affect cancer outcomes.

Influence of tumor mycobiome on cancer pathogenesis (Review).

Cancer tissues harbor a large microbiome. There is growing evidence that the tumor microbiome is significantly correlated with the prognosis of cancer patients, but the exact underlying mechanisms have remained elusive. Although the tumor mycobiome is less abundant than the biome of bacteria, it is prevalent in most cancers in humans. The present review describes in detail the impact of the tumor mycobiome on cancer pathogenesis. The tumor mycobiome promotes tumor progression and metastasis by affecting the human immune system, maintaining a pro-inflammatory environment, producing aflatoxins, attenuating cell adhesion mechanisms and fungal-bacterial interactions. Furthermore, the tumor mycobiome likewise has great potential for cancer prevention, diagnosis and treatment.

Manipulating the gut and tumor microbiota for immune checkpoint inhibitor therapy: from dream to reality.

The past decade has witnessed a revolution in cancer treatment by shifting from conventional therapies to immune checkpoint inhibitors (ICIs). These immunotherapies unleash the host immune system against the tumor and have achieved unprecedented durable remission. However, 80% of patients do not respond. This review discusses how bacteria are unexpected drivers that reprogram tumor immunity. Manipulating the microbiota impacts on tumor development and reprograms the tumor microenvironment (TME) of mice on immunotherapy. We anticipate that harnessing commensals and the tumor microbiome holds promise to identify patients who will benefit from immunotherapy and guide the choice of new ICI combinations to advance treatment efficacy.

Tumor microbiome analysis provides prognostic value for patients with stage III colorectal cancer.

Although patients with colorectal cancer (CRC) can receive optimal treatment, the risk of recurrence remains. This study aimed to evaluate whether the tumor microbiome can be a predictor of recurrence in patients with stage III CRC. Using 16S rRNA gene sequencing, we analyzed the microbiomes of tumor and adjacent tissues acquired during surgery in 65 patients with stage III CRC and evaluated the correlation of the tissue microbiome with CRC recurrence. Additionally, the tumor tissue microbiome data of 71 patients with stage III CRC from another center were used as a validation set. The microbial diversity and abundance significantly differed between tumor and adjacent tissues. In particular, Streptococcus and Gemella were more abundant in tumor tissue samples than in adjacent tissue samples. The microbial diversity and abundance in tumor and adjacent tissues did not differ according to the presence of recurrence, except for one genus in the validation set. Logistic regression analysis revealed that a recurrence prediction model including tumor tissue microbiome data had a better prediction performance than clinical factors (area under the curve [AUC] 0.846 vs. 0.679, p = 0.009), regardless of sex (male patients: AUC 0.943 vs. 0.818, p = 0.043; female patients: AUC 0.885 vs. 0.590, p = 0.017). When this prediction model was applied to the validation set, it had a higher AUC value than clinical factors in female patients. Our results suggest that the tumor microbiome of patients with CRC be a potential predictor of postoperative disease recurrence.

Tumor Microbial Communities and Thyroid Cancer Development-The Protective Role of Antioxidant Nutrients: Application Strategies and Future Directions.

Thyroid cancer (TC), the most frequent malignancy of the endocrine system, has recorded an increasing incidence in the last decades. The etiology of TC remains at least partly unknown and, among modifiable risk factors, the gut microbiota and dietary nutrients (vitamins, essential microelements, polyphenols, probiotics) have been recognized to not only influence thyroid function, but exert critical effects on TC development and progression. Recent discoveries on the existence of tumor microbiota also in the TC microenvironment provide further evidence for the essential role of tumor microorganisms in TC etiology and severity, as well as acting as prognostic markers and as a potential target of adjuvant care in the treatment of TC patients. Therefore, in this review, we summarize current knowledge on the relationship of the tumor microbiome with the clinical tumor characteristics and TC progression, also illustrating the molecular mechanisms underlying this association, and how antioxidant nutrients may be used as a novel strategy to both control gut health and reduce the risk for TC. Furthermore, we discuss how new technologies might be exploited for the development of new foods with high nutritional values, antioxidant capability, and even attractiveness to the individual in terms of sensory and emotional features.

Potential Role of the Intratumoral Microbiota in Prognosis of Head and Neck Cancer.

The tumor microbiome, a relatively new research field, affects tumor progression through several mechanisms. The Cancer Microbiome Atlas (TCMA) database was recently published. In the present study, we used TCMA and The Cancer Genome Atlas and examined microbiome profiling in head and neck squamous cell carcinoma (HNSCC), the role of the intratumoral microbiota in the prognosis of HNSCC patients, and differentially expressed genes in tumor cells in relation to specific bacterial infections. We investigated 18 microbes at the genus level that differed between solid normal tissue (n = 22) and primary tumors (n = 154). The tissue microbiome profiles of Actinomyces, Fusobacterium, and Rothia at the genus level differed between the solid normal tissue and primary tumors of HNSCC patients. When the prognosis of groups with rates over and under the median for each microbe at the genus level was examined, rates for Leptotrichia which were over the median correlated with significantly higher overall survival rates. We then extracted 35 differentially expressed genes between the over- and under-the-median-for-Leptotrichia groups based on the criteria of >1.5 fold and p < 0.05 in the Mann-Whitney U-test. A pathway analysis showed that these Leptotrichia-related genes were associated with the pathways of Alzheimer disease, neurodegeneration-multiple diseases, prion disease, MAPK signaling, and PI3K-Akt signaling, while protein-protein interaction analysis revealed that these genes formed a dense network. In conclusion, probiotics and specific antimicrobial therapy targeting Leptotrichia may have an impact on the prognosis of HNSCC.

Tumor-resident Lactobacillus iners confer chemoradiation resistance through lactate-induced metabolic rewiring

Tumor microbiota can produce active metabolites that affect cancer and immune cell signaling, metabolism, and proliferation. Here, we explore tumor and gut microbiome features that affect chemoradiation response in patients with cervical cancer using a combined approach of deep microbiome sequencing, targeted bacterial culture, and invitro assays. We identify that an obligate L-lactate-producing lactic acid bacterium found in tumors, Lactobacillus iners, is associated with decreased survival in patients, induces chemotherapy and radiation resistance in cervical cancer cells, and leads to metabolic rewiring, or alterations in multiple metabolic pathways, in tumors. Genomically similar L-lactate-producing lactic acid bacteria commensal to other body sites are also significantly associated with survival in colorectal, lung, head and neck, and skin cancers. Our findings demonstrate that lactic acid bacteria in the tumor microenvironment can alter tumor metabolism and lactate signaling pathways, causing therapeutic resistance. Lactic acid bacteria could be promising therapeutic targets across cancer types.

Bacterial and fungal characterization of pancreatic adenocarcinoma from Endoscopic Ultrasound-guided biopsies.

The tumor microbiome (TM) has been linked to pancreatic cancer prognosis. Specific microbes can confer tumor resistance to therapies. Early knowledge of the TM at time of diagnosis would be clinically relevant for precision therapy based on microbial composition. However, it is difficult to define the TM prior to surgical resection. In this pilot feasibility study, patients underwent Endoscopic Ultrasound-Fine Needle Aspiration (EUS-FNA) biopsy of pancreatic adenocarcinoma. These samples were analyzed using 16S rRNA and internal transcribed spacer (ITS) sequencing for characterization of the tumor bacteria and fungi. After in silico decontamination and comparison to non-matched tumor, we were able to characterize the TM in biopsies, which was comparable to the TM from surgical specimens. EUS-FNA biopsy may represent a feasible modality to characterize the pancreatic TM prior to surgical resection with proper decontamination strategies and improvements in matched controls.

The specific viral composition in triple-negative breast cancer tissue shapes the specific tumor microenvironment characterized on pathological images

Numerous studies have shown that different subtypes of breast cancer (BC) have significant differences in terms of the tumor microbiome, host gene expression, and histopathological image, whereas the biological links between these cancer-associated indicators are still unknown. Here, we performed a comprehensive analysis with 610 patients of the four subtypes of BC with matched tissue microbiota, host transcriptome, and histopathological image samples. Correlation analysis showed that the composition of intratumoral viruses shaped the tumor microenvironment (TME) of patients with BC, and the TME was further reflected in the histopathological images. Of the four subtypes, patients with triple-negative breast cancer (TNBC) had unique intratumoral viral community composition, non-cancer cell infiltration in the TME, and histopathological image characteristics. Furthermore, we detected multiple virus-cell-image association axes in TNBC, in which tumor-associated macrophages (TAMs) have clinical prognostic implication. This study provides a comprehensive map of the associations between the intratumoral virome, TME, and histopathological image of TNBC, as well as insights into disease prognosis that can be crucial for precise therapeutic intervention strategies.

Intratumor microbiota in cancer pathogenesis and immunity: from mechanisms of action to therapeutic opportunities.

Microbial species that dwell human bodies have profound effects on overall health and multiple pathological conditions. The tumor microenvironment (TME) is characterized by disordered vasculature, hypoxia, excessive nutrition and immunosuppression. Thus, it is a favorable niche for microbial survival and growth. Multiple lines of evidence support the existence of microorganisms within diverse types of cancers. Like gut microbiota, intratumoral microbes have been tightly associated with cancer pathogenesis. Intratumoral microbiota can affect cancer development through various mechanisms, including induction of host genetic mutation, remodeling of the immune landscape and regulation of cancer metabolism and oncogenic pathways. Tumor-associated microbes modulate the efficacy of anticancer therapies, suggesting their potential utility as novel targets for future intervention. In addition, a growing body of evidence has manifested the diagnostic, prognostic, and therapeutic potential of intratumoral microorganisms in cancer. Nevertheless, our knowledge of the diversity and biological function of intratumoral microbiota is still incomplete. A deeper appreciation of tumor microbiome will be crucial to delineate the key pathological mechanisms underlying cancer progression and hasten the development of personalized treatment approaches. Herein, we summarize the most recent progress of the research into the emerging roles of intratumoral microbiota in cancer and towards clarifying the sophisticated mechanisms involved. Moreover, we discuss the effect of intratumoral microbiota on cancer treatment response and highlight its potential clinical implications in cancer.

Association of Bacterial Composition and Diversity in the Cervical Tumor Microbiome with HPV Genotype in a Large, International Patient Cohort

Tumor bacterial composition is strongly associated with response to cancer therapy, and is impacted by environment, including geography. Human papillomavirus (HPV) genotypic diversity composition and load are dynamic during pelvic radiation (RT) and correlate with differential responses to RT in cervical cancer patients. In this multi-institutional, collaborative study, we aimed to explore associations between bacterial composition, HPV serotypes, and geographical distribution in an international patient population. Cervical swabs were collected from 287 patients diagnosed with cervical cancer/ dysplasia in four locations: Houston, USA (TX; N = 94), Ethiopia (ETH; N = 85), Puerto Rico (PR; N = 71), and Botswana (BOT; N = 37). Swabs were collected prior to treatment and were subjected to 16S V4 rRNA gene sequencing and HPV genotyping. We compared HPV types and geography via Chi-squared test. We analyzed bacterial composition, alpha diversity (ANOVA), and beta diversity (principal coordinates analysis [PCoA] with PERMANOVA) for HPV type and geography. We used Linear Discriminant Effect Size (LEfSe) analysis to distinguish taxa associated with HPV types. Overall, the global bacterial composition for patients with cancer or dysplasia did not significantly vary by location. However, the proportion of patients with each HPV type varied by location (p<0.01); HPV16 was most frequent in TX (54%), BOT (70%) and ETH (61%), while HPV18 was most frequent in PR (62%). The proportion of patients with HPV low-risk/negative tumors was highest in ETH (25%) compared to other sites (2% - 14%). Patients with HPV 16 had significantly higher bacterial alpha diversity across locations (all p<0.01). The bacterial composition also differed by HPV type across locations (p = 0.01). On LEfSe, bacterial genera enriched in HPV 16 samples were Bacteroides, Clostridium, and Prevotella. Non-HPV16 tumors were enriched in species of Lactobacillus and Gardnerella and HPV 18 and high-risk type tumors were enriched in Escherichia. In thislarge, international cohort of cervical cancer and dysplasia patients, bacterial composition was more closely associated with cervical HPV genotype than with geography. This finding has implications for the development of biomarkers and interventions aimed at improving chemotherapy and radiation response through manipulation of the microbiome.

Relationships between Microbiome and Response to Neoadjuvant Chemoradiotherapy in Rectal Cancer

Gut microbiome is known to be involved in antitumor immunotherapy and chemotherapy responses; however, few research has focused on the role of gut microbiome in the setting of concurrent chemoradiotherapy (CCRT). In this study, we investigated the tumor microbiome dynamics in patients undergoing neoadjuvant CCRT for locally advanced rectal cancer and sought to determine whether the diversity and composition of microbiome affect treatment response. A total of 103 samples from 26 patients with locally advanced rectal cancer were collected and 16S ribosomal RNA amplicon sequencing was performed. All patients underwent neoadjuvant CCRT followed by surgical resection between 2008 and 2016. Samples were obtained from both tumor and normal rectal tissue at pre- and post-CCRT. According to the American Joint Committee on Cancer tumor regression grading (TRG) system, patients were divided into responders (TRG 0, 1) and non-responders (TRG 2, 3). We performed diversity, taxonomy, and network analyses to compare responders and non-responders. Then, we established the Bayesian network model to predict treatment response in patients with rectal cancer. Overall, we detected 1260 microbial genera from 287 families, 132 orders, 56 classes, and 32 phyla in the bacteria kingdom. Between tumor and normal rectal tissues, there was no difference in microbial diversity and composition. On the other hand, there was a significant decrease in diversity and compositional alterations when comparing pre- and post-CCRT samples (all p<0.001). Ten patients (38.5%) were classified as responders and 16 patients (61.5%) were classified as non-responders. In both groups, CCRT significantly reduced microbial diversity and altered their composition, but it was more pronounced in non-responders. In taxonomic analysis of pre-CCRT samples, butyrate-producing bacteria were differentially enriched in responders. Meanwhile, in post-CCRT samples, opportunistic pathogen were overrepresented in non-responders. The network analysis revealed that butyrate-producing bacteria had strong interactions in responders, whereas opportunistic pathogen demonstrated strong interactions in non-responders (Pearson's coefficient>0.5). Finally, five microbes were selected as the optimal set for the response prediction model, which yielded an area under the curve value of 82.33%. CCRT significantly changed the diversity and composition of microbiome, especially in non-responders. Several microbes might be related with treatment response. These findings highlight the potential of microbiome to play an important role as a biomarker in patients with rectal cancer. (NCT02533271).

Comparative Analysis of Tumor Microbiome, Molecular Profile and Immune Cell Abundance by HPV Status in Head and Neck Cancers and Their Impact on Survival

Traditional clinical and molecular prognostic factors offer valuable insight into the heterogeneous natural history and treatment response of head and neck squamous cell carcinoma (HNSCC) yet fail to explain the full spectrum of observed variability. The tumor microenvironment (TME), comprising microbiome and immune cells can impact treatment response and prognosis. We analyzed The Cancer Genome Atlas (TCGA) to evaluate the association of specific microbes and genes in TME with survival and their differential expression in HPV positive (+) and HPV negative (-) HNSCC. HNSCC RNA sequencing (RNAseq) samples from TCGA were processed through the Exogenous sequencing in Tumors and Immune Cells (ExoTIC) pipeline to identify gene expression and microbial presence. HPV status was assessed by detection of papillomaviridae family of microbes. Clinical data from TCGA was extracted to compare overall survival (OS) and control for competing variables using Cox proportional hazards regression. Difference in immune cell abundance was evaluated by Kruskal-Wallis test. All statistical analysis was performed using R. A total of 498 RNAseq samples from TCGA were analyzed. Oral cavity, oropharynx, hypopharynx, and larynx tumors comprised 21.6%, 15%, 1.8%, and 22.2% of specimens, respectively. HPV was detected in 111 patients (22%), most commonly Alpha papillomavirus 9 (90.1%). Of the 5838 enriched microbes, 330 were significantly associated with OS after controlling for tumor stage, smoking, and age. Specifically, the presence of Alpha papillomavirus 9 was associated with significantly improved OS [adjusted HR = 0.60 (95% CI 0.40 - 0.89, p = 0.01)]. Microbial species found in more abundance in HPV- tumors included Citrobacter farmeri, Thermoanaerobacter kivui and Yersinia pestis which are gram negative anaerobes. Genes related to cellular transport and DNA repair were enriched while genes related to proliferation (e.g., SAGE1) were depleted in HPV+ samples. HPV- tumors had a significantly higher number of M0 (p < 0.001) and M2 macrophages (p = 0.035) while HPV+ tumors had more T regulatory cells (p < 0.001) and CD8+ T-cells (p < 0.001). Tumor microenvironment was significantly associated with survival for HNSCC patients, with particular microbes such as Alpha papillomavirus 9 correlating with improved OS. Greater abundance of certain anaerobic microbes was seen in HPV- tumors. These findings suggest TME can be used to predict patient outcomes and potentially guide personalized treatment approaches. We found an abundance of M0 and M2 macrophages in HPV- tumors, which are considered pro-tumorigenic, while anti-tumor M1 macrophages were similar in the two groups. This may help identify mechanism of resistance to immunotherapies and tailor novel immunotherapy combinations in specific patient subgroups. With further prospective research and external validation these findings have the potential to significantly impact the way we treat HNSCC in the future.

Intracellular Fusobacterium nucleatum infection attenuates antitumor immunity in esophageal squamous cell carcinoma

Currently, the influence of the tumor microbiome on the effectiveness of immunotherapy remains largely unknown. Intratumoural Fusobacterium nucleatum (Fn) functions as an oncogenic bacterium and can promote tumor progression in esophageal squamous cell carcinoma (ESCC). Our previous study revealed that Fn is a facultative intracellular bacterium and that its virulence factor Fn-Dps facilitates the intracellular survival of Fn. In this study, we find that Fn DNA is enriched in the nonresponder (NR) group among ESCC patients receiving PD-1 inhibitor and that the serum antibody level of Fn is significantly higher in the NR group than in the responder (R) group. In addition, Fn infection has an opposite impact on the efficacy of αPD-L1 treatment in animals. Mechanistically, we confirm that Fn can inhibit the proliferation and cytokine secretion of T cells and that Fn-Dps binds to the PD-L1 gene promoter activating transcription factor-3 (ATF3) to transcriptionally upregulate PD-L1 expression. Our results suggest that it may be an important therapeutic strategy to eradicate intratumoral Fn infection before initiating ESCC immunotherapies.

Relevance of tumor microbiome in cancer incidence, prognosis, and its clinical implications in therapeutics.

The microbiota is garnering progressively greater consideration as an essential facet of the tumor microenvironment that regulates tumor proliferation and affects cancer prognosis. Microbial populations that inhabit different body locations are involved in the carcinogenesis and tumor progression of their corresponding malignancies. It has been learned that the microbial populations primarily thriving within tumors are tumor-type specific. Mechanistic studies have revealed that the tumor-associated microbiota contributes to playing a pivotal role in the establishment of the tumor microenvironment, regulation of local immunity, modulation of tumor cell biology, and directly influences the therapeutic efficacy of drug treatment for tumors. This review article incorporates the pertinent studies on recent advancements in tumor microbiome studies, the interplay between the intratumor microbiota and cancer, and, discusses their role and mechanism of action in the emergence and treatment of cancer, and their relationship to clinical characteristics.