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PORPHYROMONAS GINGIVALIS SUPPORTS COLON CANCER PROGRESSION BY SWITCHING INKT CELL FUNCTIONS TOWARDS A PRO-TUMORIGENIC PHENOTYPE

Federica Facciotti 1, Angelica Julieth Diaz Basabe 2, Georgia Lattanzi 3, Fiorenzo Botti 4, Gianluca Lopez 3, Maurizio Vecchi 3, Flavio Caprioli 5, Francesco Strati 1

Affiliations

1 University of MIlano-Bicocca, Milan, Italy

2 European Institute of Oncology IRCCS, Milan, Italy

3 Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico University of Milan, Milan, Italy

4 Fondazione Irccs Ca' Granda Ospedale Maggiore Policlinico - Università degli Studi di Milano, Lissone, Italy

5 University of Milan, Milano, Italy

Summary

AI Generated

Porphyromonas gingivalis promotes colorectal cancer tumorigenesis by reprogramming invariant Natural Killer T cells from antitumor effectors to pro-tumorigenic cytokine producers in vitro and in a mouse model.

Compared to αGalCer stimulation, P. gingivalis-primed human iNKT cells showed lower interferon gamma levels, impaired cytotoxicity against CRC cell lines, and increased expression of GM-CSF, IL-17, and IL-10.
In AOM/DSS-treated mice, P. gingivalis administration resulted in larger tumors and increased IL-17+ and GM-CSF+ iNKT cells.
P. gingivalis-primed iNKT cells exhibited an enriched neutrophil chemotaxis gene signature including CXCL1, CXCL2, CXCL5, CXCL8, CCL2, and CCL4, and showed increased capability of neutrophil chemotaxis.
The study used 16S rRNA gene sequencing of tumor-associated mucosal microbiota from 35 CRC patients and found P. gingivalis present in a large fraction, prompting investigation of this oral pathobiont's effects on iNKT cell function.

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This summary was generated by an AI large language model based on the content transcript. It is for informational purposes only and should not be considered a substitute for clinical judgment. Always rely on your professional expertise and the full clinical context when making clinical decisions.

Abstract

Introduction

Invariant Natural Killer T (iNKT) cells are lipid-specific T lymphocytes endowed with antitumor activities and whose infiltration is considered a positive prognostic factor in colorectal cancer (CRC). In this context, we have previously demonstrated that, at steady state, iNKT cells eliminate human CRC cells by releasing perforin and granzyme B (1).
However, we reported that the tumor-associated pathobiont Fusobacterium nucleatum is capable of inducing IL17 and GM-CSF expression in iNKT cells, promoting iNKT-mediated recruitment of neutrophils with PMN-MDSCs- like phenotype and functions. Tumor co-infiltration by iNKT cells and neutrophils in a large cohort CRC patients of correlates with negative clinical outcomes (2). Since the gut microbiota is an oncogenic driver of CRC and intestinal microbes represent potent stimulators of iNKT cell responses we analyzed the tumor-associated mucosal microbiota of the 35 CRC patients by 16S rRNA gene sequencing, revealing the presence in a large fraction of patients of Porphyromonas gingivalis, an opportunistic oral pathobiont often associated with inflammatory diseases and cancers.

Aims & Methods

Very little is known about how the function of iNKT cells is influenced by Porphyromonas gingivalis. Our aim is to assess changes in human iNKT cell phenotype and function provoked by this bacterium, and how these changes might contribute to colon cancer progression.
Human iNKT cell phenotype, functional profile and cytotoxic capabilites were evaluated upon stimulation with P. gingivalis isolates in vitro. Subsequently, as validation, P. gingivalis was administered to AOM/DSS-treated mice and evaluated iNKT cell phenotype and tumor progression. P. gingivalis-exposed human iNKT cells were sequenced and candidate molecules were tested in vitro in killing assays with human CRC epithelial cells.

Results

We observed that, compared to cells stimulated with aGalCer (a prototypical iNKT cell antigen), iNKT cells primed with P. gingivalis showed lower levels of interferon gamma, together with impaired cytotoxicity against CRC cell lines. These cells were also characterized by an increased expression of GM-CSF, and interleukins -17 and -10, as well as an increased capability of neutrophil chemotaxis. This pro-tumorigenic phenotype was confirmed in AOM/DSS-treated mice, as P. gingivalis-treated animals showed tumors of greater size, together with an increase in IL-17+ and GM-CSF+ iNKT cells. Pg-primed iNKT cells showed an enriched neutrophil chemotaxis gene signature, which included the chemokines CXCL1, CXCL2, CXCL5, CXCL8, CCL2 and CCL4 and of proinflammatory proteins acting on the cytotoxic machinery of NKT cells inhibiting their killing functions.

Conclusion

These results demonstrate that P. gingivalis can promote colon tumorigenesis by acting on iNKT cells, both by hampering antitumor properties and promoting the release of pro-tumorigenic cytokines and chemokines, which further act on myelo-phagocytic cells.

References

Díaz-Basabe, A., et al. (2021). Human intestinal and circulating invariant natural killer T cells are cytotoxic against colorectal cancer cells via the perforin–granzyme pathway. Mol Oncol, 15: 3385-3403. https://doi.org/10.1002/1878-0261.13104

Conference

UEG Week Copenhagen 2023

Topics

Colorectal

Submission format

Abstract

Session

Gut microbiome: From mechanisms to disease (Posters)

Citation

United European Gastroenterology Journal 2023; 11 (Supplement 8)

Published

2023

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PROFILE TRIAL 5-YEAR FOLLOW-UP SHOWS EARLY “TOP-DOWN” ANTI-TNF THERAPY RESULTS IN HIGH TREATMENT DURABILITY AND MODIFIES THE COURSE OF CROHN’S DISEASE

Nurulamin Noor 1, Mohmmed Tauseef Sharip 1, Haiyan Zheng 2, Barry Widmer 3, Biljana Brezina 1, Kamal Vijaykant Patel 4, Francis Dowling 5, Suhaylah Bhatti 5, Nadia Alsmade 5, Tariq Ahmad 6, Paul Banim 7, James Berrill 8, Rachel Cooney 9, Juan de la Revilla Negro 1, Shanika De Silva 10, Shahida Din 11, Dharmaraj Durai 12, John Gordon 13, Ailsa L Hart 14, Peter Irving 15, Matthew Johnson 16, Alexandra Kent 17, Bel Klaartje Kok 18, Gordon Moran 19, Craig Mowat 20, Pritash Patel 21, Tim Raine 1, Rebecca Saich 22, Dan Sharpstone 23, Melissa Smith 24, Alan Steel 25, Sreedhar Subramanian 1, Alan Wiles 26, Horace Williams 27, James O. Lindsay 18, Nicholas A Kennedy 6, Eoin F. McKinney 28, Paul A Lyons 28, Kenneth Smith 29, James C. Lee 30, David Robertson 31, Miles Parkes 1

Affiliations

1 Cambridge University Hospitals, Cambridge, United Kingdom

2 University of Bath, Bath, United Kingdom

3 University of Cambridge, Cambridge, United Kingdom

4 St George's Hopsital, London, United Kingdom

5 Cambridge Clinical Trials Unit, Cambridge, United Kingdom

6 Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom

7 James Paget Hospital, Great Yarmouth, United Kingdom

8 Royal Glamorgan Hospital, Llantrisant, United Kingdom

9 University Hospital Birmingham, Birmingham, United Kingdom

10 Russells Hall Hospital, Dudley, United Kingdom

11 Western General Hospital, Edinburgh, United Kingdom

12 University Hospital of Wales, Cardiff, United Kingdom

13 Royal Hampshire County Hospital, Winchester, United Kingdom

14 St Mark’s Hospital and Academic Institute, Harrow, United Kingdom

15 Guy´s and St Thomas´ Hospital, London, United Kingdom

16 The Luton & Dunstable University Hospital, Luton, Bedfordshire, United Kingdom

17 Kings College Hospital NHS Trust, London, United Kingdom

18 The Royal London Hospital - Barts Health NHS Trust, London, United Kingdom

19 Nottingham Digestive Diseases Centre, Nottingham, United Kingdom

20 Ninewells Hospital and Medical School, Dundee, United Kingdom

21 Epsom and St Helier University Hospitals, Carshalton, United Kingdom

22 Basingstoke and North Hampshire Hospital, Basingstoke, United Kingdom

23 West Suffolk NHS Foundation Trust, Bury St Edmunds, United Kingdom

24 University Hospitals Sussex NHS Foundation Trust, Brighton, United Kingdom

25 Royal Liverpool Hospital, Liverpool, United Kingdom

26 The Queen Elizabeth Hospital, Kings Lynn, United Kingdom

27 Imperial College Healthcare NHS Trust, London, United Kingdom

28 University of Cambridge, School of Clinical Medicine, Cambridge, United Kingdom

29 University of Melbourn, Melbourne, Australia

30 The Francis Crick Institute, London, United Kingdom

31 MRC Biostatistics Unit, Cambridge, United Kingdom