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Parvimonas micra is associated with tumour immune profiles in molecular subtypes of colorectal cancer
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
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2022 (English)In: Cancer Immunology and Immunotherapy, ISSN 0340-7004, E-ISSN 1432-0851, Vol. 71, p. 2565-2575Article in journal (Refereed) Published
Abstract [en]

The importance of the tumour microbiome in different aspects of colorectal cancer (CRC) has been increasingly recognised, but many questions remain. The aim of this study was to explore the effect of specific CRC associated microbes on the tumour immune response, which has a considerable prognostic value in CRC. We applied specific qPCR to detect Parvimonas micra and Fusobacterium nucleatum in tumour tissues from an immunologically well-characterised cohort of 69 CRC patients. This cohort included detailed analyses of immune profiles based on flow cytometry and transcriptomics in tumour tissue and blood, along with comprehensive analyses of molecular subtypes. P. micra and F. nucleatum were detected in 24% and 64% of tumour tissues, respectively. We found a significant association of P. micra with high-grade tumours and tumours of CMS1 subtype. F. nucleatum was significantly associated with right-sided tumours, microsatellite instability, and CMS1 tumours. The immunological analyses revealed significant associations of P. micra with activated CD69+ T lymphocytes and increased antigen-presenting HLA-DR+ B lymphocytes. P. micra was also positively associated with M1 and M2 macrophage traits. The impact of P. micra tumour colonisation on the immune response was further assessed using transcriptomics in validation of our findings. No associations were found between F. nucleatum and immune profiles in this study. Our findings support novel associations between P. micra and the immune response in CRC. A better understanding of these interactions might help to identify important predictive and prognostic tools as well as new targets for therapy.

Place, publisher, year, edition, pages
Springer, 2022. Vol. 71, p. 2565-2575
Keywords [en]
Colorectal cancer, F. nucleatum, Immunity, Mucosal microbiota, P. micra
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-193335DOI: 10.1007/s00262-022-03179-4ISI: 000770199300001PubMedID: 35301576Scopus ID: 2-s2.0-85126450770OAI: oai:DiVA.org:umu-193335DiVA, id: diva2:1647763
Funder
Cancerforskningsfonden i Norrland, AMP 21-1048Region Västerbotten, VLL-833541Swedish Cancer Society, 20 1271PjFAvailable from: 2022-03-28 Created: 2022-03-28 Last updated: 2024-03-26Bibliographically approved
In thesis
1. Gut microbiota in colorectal cancer: The importance of Parvimonas micra
Open this publication in new window or tab >>Gut microbiota in colorectal cancer: The importance of Parvimonas micra
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Tarmfloran hos patienter med kolorektalcancer : betydelsen av Parvimonas micra
Abstract [en]

Colorectal cancer (CRC) is a heterogenous disease consisting of multiple molecular subtypes, each of which has diverse treatment responses and prognoses. The importance of the gut microbiota in CRC development and progression has undergone increasing recognition in recent years, with a structural segregation in terms of microbial composition between CRC patients and healthy controls. However, many questions remain before a full understanding of the impact of the gut microbiota on CRC is reached. The overall aim of this thesis was to explore the role of gut microbes in CRC, including their potential as CRC biomarkers and associations with clinicopathological, immunological, and molecular traits of CRC. A particular focus was the CRC-associated oral pathogen Parvimonas micra.

To investigate faecal microbiota as a potential biomarker for CRC, we studied the presence of specific bacteria in faeces from CRC patients and controls using qPCR. We found higher levels of P. micra in faecal samples from CRC patients than from control patients. A test for high levels of P. micra was able to identify CRC with a specificity of 87.3% and a sensitivity of 60.5%. Adding the oral pathogen Fusobacterium nucleatum, colibactin-producing bacteria, and faecal haemoglobin to the test enhanced its sensitivity.

We further aimed to explore the associations of P. micra and F. nucleatum with molecular subtypes of CRC and the tumour immune response. The levels of P. micra and F. nucleatum, as analysed by qPCR in both faeces and tumour tissue from CRC patients, were found to be positively correlated. High levels of intratumoural P. micra and F. nucleatum were associated with tumours of the microsatellite instable subtype and BRAF-mutated tumours. For F. nucleatum, an additional association with right-sided tumours was found. Moreover, both P. micra and F. nucleatum in tumour tissue were associated with the immune-activated consensus molecular subtype (CMS) 1 subtype of CRC. In line with this finding, we found novel associations between intratumoural P. micra and specific immune traits, which were evaluated by flow cytometry, indicating an active immune response in CRC. These results were further confirmed using transcriptomics. However, no associations with specific immune traits were found for F. nucleatum.

We also investigated associations between faecal and intratumoural levels of P. micra and F. nucleatum and survival in CRC patients. CRC patients with high levels of intratumoural P. micra and F. nucleatum showed reduced five-year cancer-specific survival. This association remained significant for P. micra in multivariable analysis. No associations with cancer-specific survival were found for levels of P. micra and F. nucleatum in faeces.

To investigate the faecal microbial landscape of CRC patients on a larger scale, we used 16S rRNA sequencing. Network analysis revealed a cluster of associated bacteria, including P. micra and F. nucleatum, as well as other CRC-related pathogens such as Bacteroides fragilis, Peptostreptococcus stomatitis, and Porphyromonas spp. Furthermore, beta-diversity analysis indicated a significantly different gut microbial composition depending on tumour location and microsatellite instability status. Interestingly, three of the six annotated species most strongly associated with microsatellite instable tumours were also present in the cluster: P. micra, F. nucleatum, and P. stomatis.

In conclusion, our results suggest P. micra as a putative candidate for a future non-invasive microbial test panel for detection of CRC. Moreover, our results indicate that intratumoural P. micra and F. nucleatum are associated with immune-active subtypes of CRC, including microsatellite instable tumours and tumours of the CMS1 subtype, as well as decreased patient survival. Furthermore, P. micra and F. nucleatum were found to be associated with a cluster of other CRC-related oral pathogens. An improved understanding of the role of the gut microbiota in tumour progression may lead to the identification of important biomarkers for CRC disease and outcome, as well as potential targets for future therapy.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2024. p. 53
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2286
Keywords
Colorectal cancer, mucosal microbiota, Parvimonas micra, Fusobacterium nucleatum, immunity, survival
National Category
Biomedical Laboratory Science/Technology
Research subject
biomedical laboratory science
Identifiers
urn:nbn:se:umu:diva-222737 (URN)978-91-8070-300-0 (ISBN)978-91-8070-299-7 (ISBN)
Public defence
2024-04-26, Hörsal Betula, byggnad 6M, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2024-04-05 Created: 2024-03-26 Last updated: 2024-03-28Bibliographically approved

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Löwenmark, ThyraLi, XingruLöfgren Burström, AnnaZingmark, CarlLing, AgnesKellgren, Therese G.Larsson, PärLjuslinder, IngridWai, Sun NyuntEdin, SofiaPalmqvist, Richard

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Löwenmark, ThyraLi, XingruLöfgren Burström, AnnaZingmark, CarlLing, AgnesKellgren, Therese G.Larsson, PärLjuslinder, IngridWai, Sun NyuntEdin, SofiaPalmqvist, Richard
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PathologySection of MedicineOncologyDepartment of Molecular Biology (Faculty of Medicine)
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