Microbiota On Chip (MOC).
Despite unprecedented success in treating cancer, responses to immune checkpoint inhibitors (ICI) are heterogeneous and influenced by multiple environmental factors, including the gastrointestinal (gut) microbiome. Animal models have been extensively used to address microbiome-host molecular interactions but, in addition to interspecies differences, the lack of a rapid, robust and accessible experimental model still remains a major obstacle to efficiently stratifying patients by response and implementing therapeutic manipulation of the microbiome. We developed and applied a 3D microfluidic-based device equipped with a peristaltic-like movement to reliably predict the clinical outcome of ICI therapy based on fecal microbiota’s testing. We provide evidence for the biological relevance of the model compared to mice and perform detailed mechanistic studies to uncover epithelium-specific biomarkers and microbial factors that correlate with the clinical outcome in melanoma patients and that may represent targets for future prognostic testing and therapeutic interventions.
We are actively working to further develop this model for IO studies.
Immunotherapy on our new gut-on-a-chip (Nat Biomed Eng) H2020 SINERGIAMicrobiome Immune Oncology (MIO).
We recently completed the first multicentric long-term longitudinal study of the gut microbiome on patients with advanced melanoma undergoing ICB, following them from pre-ICB up to 13 months of treatment in an adjuvant setting. Thanks to our unique study design, we revealed that microbiome dynamic during immunotherapy correlates with clinical response, with responders carrying distinctly stable microbes in their gut that associates with low neutrophils-to-lymphocytes ratio (NLR) and high levels of IL-12p70, two systemic markers of response. Importantly, our finding indicates that, rather than the presence or abundance of individual taxa, the stability of microbial functions over time holds exceptional prognostic value, a concept that implies the presence of response-relevant microbial functions since baseline and that we have validated by effectively stratifying patients across multiple international cohorts.
In addition, we have discovered MHC class I-restricted peptides derived from flagellin-related gene families (FLach) that are stably present in patients with melanoma responding to ICB and mimic tumor-associated antigens. Strikingly, FLach induce reactivity on peripheral blood mononucleated cells (PBMC) and tumor infiltrating lymphocytes (TIL) from responders, supporting the idea that these patients have a pre-ICB immunity directed against them. Moreover, FLach enhance CD8+ tumor killing, unlocking new therapeutic possibilities.
We are now expanding these concept across other tumor types, with the ultimate goal of improving patient's stratification and craft innovative microbiome-based therapeutics.
Microbiome Dynamic and Molecular Mimicry in Immunotherapy (Cell H&M) MIO on microbioma.itMicrobiota-Immune system-Tumor Interaction in Colorectal Oncology (MITICO).
About 40-50% of patients treated for loco-regional colorectal cancer (CRC) relapse and ultimately die from metastatic disease. Despite being considered a ”hot” tumor, where infiltrating lymphocytes are independent positive predictor of survival, only a small fraction of CRC patients respond to immune checkpoint inhibitors (ICI).
This project originates from two milestone discoveries. First, the gut microbiome is key to modulate the response to ICI, but the overlap across different cohorts is mostly functional rather than compositional. Second, the metabolic constrains imposed by the tumor microenvironment heavily impact the anti-tumor activity of CD8+ T cells in solid tumors not responsive to ICI. Thus, we hypothesize that therapeutic manipulation of the metabolic output of mucosal bacteria can reshape the TME and improve the response of CRC to ICI.
The project has three main objectives:
. Quantification of significant metabolite’s alterations and reconstruction of bacterial metabolic pathways responsible for their production in tumors and their surrounding tissues from CRC patients
. Molecular characterization of the immunomodulatory impact of the microbiota, linking the mucosal microbiota to the immune cells infiltrating the tumor or circulating in periphery to define new combinatory biomarkers and potential therapeutic targets;
. Mechanistic validation and improvement of response to ICI based on experimental manipulations of the microbial metabolic output on a new patient-derived organ-on-chip device.
This study will enable multi-scale profiling and predictive modelling on a large and fully annotated cohort while simultaneously spawning novel potential therapeutic targets for intervention.
Team MITICO sparks its first study (Nat Comm) Why does location matter in CRC? MITICO Team contribution (Gen Med) AIRC is on our side Our studies got support from WWCR Carlotta Catozzi recipient of 2023 FUV fellowship FUV supporting MITICO Donate to MITICO project
Microbiome in gastroesophageal tumors (MIMETIC)
Gastric adenocarcinoma (GA) represents a leading cause of cancer death worldwide. However, current biomarkers are insufficient to guide treatment choices, leading to unsatisfactory therapy efficacy. As a key modulator of host immune response, the gut microbiota may represent a valuable biomarker while providing actionable targets to improve patient's treatment. We are working to map correlations between nutrition, microbiome, genomics and radiomics and to correlate them whit the clinical outcome.
We are conducting a prospective observational trial in GA patients, candidate to receive peri-operative chemoterapy or upfront surgery. For each patient, we longitudinally collect blood, fecal and salivary samples, alongside with clinical and nutritional information. Additionally, past dietary consumption is measured using the food frequency questionnaire (FFQ). At baseline, CT scan for staging, radiomic analysis and upper digestive endoscopy with biopsy for diagnosis, and molecular biomarkers are performed. Additional samples are taken from tumor and surrounding normal mucosa for transcriptome and microbiome analysis, which will be correlated with clinical and radiomic data.
Enrolment has been completed and we are now finalizing follow up, data analysis and mechanistic studies.