Effect of prior antibiotic or chemotherapy treatment on immunotherapy response in non-small cell lung cancer.

BACKGROUND: Treatment outcomes of advanced non-small cell lung cancer (NSCLC) have substantially improved with immune checkpoint inhibitors (ICI), although only approximately 19% of patients respond to immunotherapy alone, increasing to 58% with the addition of chemotherapy. The gut microbiome has been recognized as a modulator of ICI response via its priming effect on the host immune response. Antibiotics as well as chemotherapy reduce gut microbial diversity, hence altering composition and function of the gut microbiome. Since the gut microbiome may modify ICI efficacy, we conducted a retrospective study evaluating the effects of prior antibiotic or chemotherapy use on NSCLC patient response to ICI. METHODS: We retrospectively evaluated 256 NSCLC patients treated between 2011-2017 at Moffitt Cancer Center with ICI ± chemotherapy, examining the associations between prior antibiotic or chemotherapy use, overall response rate and survival. Relative risk regression using a log-link with combinatorial expectation maximization algorithm was performed to analyze differences in response between patients treated with antibiotics or chemotherapy versus patients who didn't receive antibiotics or chemotherapy. Cox proportional hazards models were constructed to evaluate associations between risk factors and overall survival. RESULTS: Only 46 (18% of 256) patients used antibiotics prior to and/or during ICI treatment, and 146 (57%) had prior chemotherapy. Antibiotic users were 8% more likely to have worse overall response rate (RR:1.08; CI:0.93-1.26; p = 0.321), as well as a 35% worse overall survival (HR:1.35; CI:0.91-2.02; p = 0.145), although results were not statistically significant. However, prior use of chemotherapy was significantly associated with poor ICI response (RR:1.24; CI:1.05-1.47; p = 0.013) and worse overall survival (HR:1.47; CI:1.07-2.03; p = 0.018). CONCLUSIONS: Patients receiving antibiotics prior to and/or during ICI therapy might experience worse treatment outcomes and survival than unexposed patients, although these associations were not statistically significant and hence warrant further prospective study. Prior chemotherapy significantly reduced ICI response and overall survival. Antibiotic or chemotherapy exposure may negatively impact ICI response, perhaps through disruption of the eubiotic gut microbiome.

Changing the Game: College Dance Training for Well-Being and Resilience Amidst the COVID-19 Crisis.

The COVID-19 pandemic has disrupted all aspects of life, from health to financial to social. College students in particular have faced difficulties adjusting to an entirely virtual atmosphere, compounding the normal stressors that come with full class loads and transitioning into more independent adult lives. In response to the onset of the COVID-19 crisis, a faculty member at the University of South Florida's College of Public Health designed impromptu, free dance lessons offered through a virtual video platform to the college and broader community. The lessons were offered with the intent of providing a healthy and engaging environment to help students and others in the community cope with lockdown stress, depression, and anxiety throughout spring and summer 2020. This article summarizes the structure of the intervention, lessons learned throughout implementation, and the broader practice potential during the COVID-19 pandemic and beyond.

A Customized At-Home Stool Collection Protocol for Use in Microbiome Studies Conducted in Cancer Patient Populations.

Fecal specimen collection in the clinical setting is often unfeasible for large population studies, especially because cancer patients on immunotherapy often experience constipation. A method for constructing and using an at-home stool collection kit designed for epidemiological studies in cancer patients is presented. Participation and compliance rates of the collection kit among late-stage cancer patients from an ongoing, longitudinal study are also discussed. The kit includes three different media on which samples are introduced. Using one stool sample, patients collect specimens by smearing stool onto a fecal occult blood test (FOBT) card, containing three slides for collection. Additional specimens from the same stool sample are added to one tube containing 8 mL of RNAlater preservative and one tube containing 8 mL of 95% ethanol. Stool specimens are stored at room temperature and returned to researchers within 3 days of collection. The purpose of this kit is to yield stool specimens on a variety of media that can be preserved for extended periods of time at room temperature and are compatible with multi-omics approaches for specimen analysis. According to leading microbiome researchers and published literature, each collection method is considered optimal for use in large epidemiological studies. Moreover, the kit is comprised of various components that make stool collection easy, so as not to burden the patient and hence maximize overall compliance. Use of this kit in a study of late-stage lung cancer patients had a participation rate of 83% and baseline compliance rate of 58%.

High Pretreatment DHEA Is Associated with Inferior Immunotherapy Response in Metastatic Non-Small Cell Lung Cancer.

Background: Sex difference in the immune response may influence patients' response to immune checkpoint inhibitors (ICIs). We conducted a prospective observation study to determine the correlation between pretreatment sex hormone levels and response to ICIs in metastatic non-small cell lung cancer (NSCLC). Method: Pretreatment plasma samples from 61 patients with newly diagnosed NSCLC prior to ICI therapy were collected. Six sex hormone levels [pyrazole triol, 17 ß-estradiol, 5-androstenediol, 3ß-androstenediol, dehydroepiandrosterone (DHEA), and S-equol] were measured using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). Overall survival (OS) and progression-free survival (PFS) were compared between the high- and low-level groups in the whole cohort. Result: Among the six sex hormones measured, DHEA levels were significantly higher among patients without clinical benefits in the discovery cohort; the remaining sex hormones did not differ significantly. In the whole cohort, median PFS was 22 months for patients with low DHEA levels vs. 3.8 months for those with high DHEA [hazard ratio, 14.23 (95% CI, 4.7-43); p < 0.001]. A significant association was also observed for OS [hazard ratio, 8.2 (95% CI, 2.89-23.35); p < 0.0001]. Conclusions: High pretreatment plasma DHEA levels were associated with poor clinical outcomes for patients with metastatic NSCLC treated with ICIs.

Gut microbiome and cancer implications: Potential opportunities for fermented foods.

There is a critical opportunity to improve response to immunotherapies and overall cancer survivorship via dietary interventions targeted to modify the gut microbiome, and in turn, potentially enhance anti-cancer immunity. A promising dietary intervention is fermented foods, which may alter gut microbiome composition and, in turn, improve immunity. In this article, we summarize the state of the literature pertaining to the gut microbiome and response to immunotherapy and other cancer treatments, potential clinical implications of utilizing a fermented foods dietary approach to improve cancer treatment outcomes, and existing gaps in the literature regarding the implementation of fermented food interventions among individuals with cancer or with a history of cancer. This review synthesizes a compelling rationale across different disciplines to lay a roadmap for future fermented food dietary intervention research aimed at modulating the gut microbiome to reduce cancer burden.

Prospective and Cross-sectional Associations of the Rectal Tissue Microbiome with Colorectal Adenoma Recurrence.

BACKGROUND: The gut microbiome is plausibly associated with colorectal cancer risk; however, previous studies mostly investigated this association cross-sectionally. We investigated cross-sectional and prospective associations of the rectal tissue microbiome with adenoma recurrence in the Polyp Prevention Trial (PPT). METHODS: PPT is a 4-year randomized clinical trial of the effect of a dietary intervention on adenoma recurrence among community members. We extracted DNA from rectal biopsies at baseline, end of year 1, and end of year 4 among 455 individuals and sequenced the V4 region of the 16S rRNA gene. At each timepoint, we investigated associations of alpha diversity, beta diversity, and presence and relative abundance of select taxa with adenoma recurrence using multivariable logistic regression. RESULTS: Variation in beta diversity was primarily explained by subject and minimally by year of collection or time between biopsy and colonoscopy. Cross-sectionally, year 4 alpha diversity was strongly, inversely associated with adenoma prevalence [ORQ3 vs. Q1 Shannon index = 0.40 (95% confidence interval, CI: 0.21-0.76)]. Prospective alpha diversity associations (i.e., baseline/year 1 alpha diversity with adenoma recurrence 3-4 years later) were weak or null, as were cross-sectional and prospective beta diversity-adenoma associations. Bacteroides abundance was more strongly, positively associated with adenoma prevalence cross-sectionally than prospectively. CONCLUSIONS: Rectal tissue microbiome profiles may be associated with prevalent adenomas, with little evidence supporting prospective associations. IMPACT: Additional prospective studies, with serial fecal and tissue samples, to explore microbiome-colorectal cancer associations are needed. Eventually, it may be possible to use microbiome characteristics as intervenable risk factors or screening tools.

Effects of Green Tea Catechins on Prostate Cancer Chemoprevention: The Role of the Gut Microbiome.

Accumulating evidence supports green tea catechins (GTCs) in chemoprevention for prostate cancer (PCa), a leading cause of cancer morbidity and mortality among men. GTCs include (-)-epigallocatechin-3-gallate, which may modulate the molecular pathways implicated in prostate carcinogenesis. Prior studies of GTCs suggested that they are bioavailable, safe, and effective for modulating clinical and biological markers implicated in prostate carcinogenesis. GTCs may be of particular benefit to those with low-grade PCas typically managed with careful monitoring via active surveillance (AS). Though AS is recommended, it has limitations including potential under-grading, variations in eligibility, and anxiety reported by men while on AS. Secondary chemoprevention of low-grade PCas using GTCs may help address these limitations. When administrated orally, the gut microbiome enzymatically transforms GTC structure, altering its bioavailability, bioactivity, and toxicity. In addition to xenobiotic metabolism, the gut microbiome has multiple other physiological effects potentially involved in PCa progression, including regulating inflammation, hormones, and other known/unknown pathways. Therefore, it is important to consider not only the independent roles of GTCs and the gut microbiome in the context of PCa chemoprevention, but how gut microbes may relate to individual responses to GTCs, which, in turn, can enhance clinical decision-making.

Circulating Bile Acids and Adenoma Recurrence in the Context of Adherence to a High-Fiber, High-Fruit and Vegetable, and Low-Fat Dietary Intervention.

INTRODUCTION: Diet may affect bile acid (BA) metabolism and signaling. In turn, BA concentrations may be associated with cancer risk. We investigated (i) associations of BA concentrations with adenoma recurrence and (ii) the effect of a high-fiber, high-fruit and vegetable, and low-fat dietary intervention on serum BA concentrations. METHODS: The Polyp Prevention Trial is a 4-year randomized, controlled trial that investigated the effect of a high-fiber, high-fruit and vegetable, and low-fat diet on colorectal adenoma recurrence. Among 170 participants who reported adhering to the intervention and 198 comparable control arm participants, we measured 15 BAs in baseline, year 2, and year 3 serum using targeted, quantitative liquid chromatography-tandem mass spectrometry. We estimated associations of BAs with adenoma recurrence using multivariable logistic regression and the effect of the dietary intervention on BA concentrations using repeated-measures linear mixed-effects models. In a subset (N = 65), we investigated associations of BAs with 16S rRNA gene sequenced rectal tissue microbiome characteristics. RESULTS: Baseline total BA concentrations were positively associated with adenoma recurrence (odds ratio Q3 vs Q1 = 2.17; 95% confidence interval = 1.19-4.04; Ptrend = 0.03). Although we found no effect of the dietary intervention on BA concentrations, pretrial dietary fiber intake was inversely associated with total baseline BAs (Spearman = -0.15; PFDR = 0.02). BA concentrations were associated with potential colorectal neoplasm-related microbiome features (lower alpha diversity and higher Bacteroides abundance). DISCUSSION: Baseline circulating BAs were positively associated with adenoma recurrence. Although the dietary intervention did not modify BA concentrations, long-term fiber intake may be associated with lower concentrations of BAs that are associated with higher risk of adenoma recurrence.

Interaction of bacterial genera associated with therapeutic response to immune checkpoint PD-1 blockade in a United States cohort.

BACKGROUND: Recent studies show that human gut microbial composition can determine whether a patient is a responder or non-responder to immunotherapy but have not identified a common microbial signal shared by responding patients. The functional relationship between immunity, intestinal microbiota, and NSCLC response to immune checkpoint inhibitor/inhibition (ICI) in an American cohort remains unexplored. METHODS: RNAlater-preserved fecal samples were collected from 65 pre-treatment (baseline) and post-treatment stage III/IV NSCLC patients undergoing ICI therapy, categorized as responders or non-responders according to RECIST criteria. Pooled and individual responder and non-responder microbiota were transplanted into a gnotobiotic mouse model of lung cancer and treated with ICIs. 16S rDNA and RNA sequencing was performed on patient fecal samples, 16S rDNA sequencing on mouse fecal samples, and flow cytometric analysis on mouse tumor tissue. RESULTS: Responder patients have both a different microbial community structure than non-responders (P = 0.004) and a different bacterial transcriptome (PC2 = 0.03) at baseline. Taxa significantly enriched in responders include amplicon sequence variants (ASVs) belonging to the genera Ruminococcus, Akkermansia, and Faecalibacterium. Pooled and individual responder microbiota transplantation into gnotobiotic mice decreased tumor growth compared to non-responder colonized mice following ICI (P = 0.023, P = 0.019, P = 0.008, respectively). Responder tumors showed an increased anti-tumor cellular phenotype following ICI treatment. Responder mice are enriched with ASVs belonging to the genera Bacteroides, Blautia, Akkermansia, and Faecalibacterium. Overlapping taxa mapping between human and mouse cohorts correlated with tumor size and weight revealed a network highlighting responder-associated ASVs belonging to the genera Colidextribacter, Frisingicoccus, Marvinbryantia, and Blautia which have not yet been reported. CONCLUSIONS: The role of isolate-specific function and bacterial gene expression in gut microbial-driven responsiveness to ICI has been underappreciated. This work supports further investigation using isolate-driven models to characterize the mechanisms underlying this phenomenon.