Colorectal cancer (CRC) is among the most frequent tumor types and is a leading cause of cancer-related death. Tumor infiltration by defined types of immune cells has been recently recognized to favor prolonged survival. However, immune cell infiltration spontaneously occurs in a minority of cases, below 20% . No therapy capable of enhancing immune cell recruitment into tumor tissues is currently available.
In recent studies we found that some commensal bacteria, normally present in the intestinal flora, the so-called microbiome, have the ability to stimulate tumor cells to produce chemotactic factors capable of attracting immune cells into tumor tissues. Upon analysis of the gut flora composition of human CRC samples, we have identified a group of bacterial specie which are associated with high expression of chemokines, high densities of tumor infiltrating cells, and prolonged patients’ survival.
These findings suggest the potential therapeutic administration of identified bacteria to increase CRC infiltration by immune cells, thereby improving clinical outcome. With the present project, we aimed at selecting the most effective bacterial species and combinations for subsequent clinical application.
What is special about the project?
This the first study evaluating the potential therapeutic application of bacterial species found to be associated with favorable clinical outcome in patients with CRC. The newly developed microbiome-based treatment might represent a valid innovative therapy for patients suffering from CRC, estimated, based on published data, as >1 M patients per year worldwide. Enhancement of immune infiltration in CRC upon bacteria-based therapy is expected to increase recurrence free and overall survival in early stage CRCs. Moreover, in advanced CRC cases, it might increase response rates to standard chemotherapies or emerging immunotherapies.
The project is being implemented within the newly established Translational Research group of the Department of Surgery, of the Ente Ospedaliero Cantonale, strategically embedded within the Institute of Research of Biomedicine, in close contact with other groups of prominent oncologists and immunologists. In the first two years of funding, we have investigated the capacity of individual bacterial species to induce in tumor cells the expression of chemokines recruiting immune cells into tumor tissues. We have identified a group of five bacterial species effectively inducing in tumor cells upregulation of chemokine genes in vitro. We have recently started to test the ability of these bacteria to promote recruitment of immune cells into tumors, in an experimental CRC model. Preliminary results indicate that administration of at least one of the tested bacterial species leads to enhanced intra-tumoral recruitment of immune cells and reduced tumor development. We next intend to assess whether the increased immune infiltration promoted by bacteria administration may result in enhanced effectiveness immunotherapies based on immunological checkpoint inhibitors.
Droeser RA, Iezzi G. IL-22-mediates Cross-talk between Tumor Cells and Immune Cells Associated with Favorable Prognosis in Human Colorectal Cancer. J Cell Immunol. 2021;3:118-121.
Tosti N, Cremonesi E, Governa V, Basso C, Kancherla V, Coto-Llerena M, Amicarella F, Weixler B, Däster S, Sconocchia G, Majno PE, Christoforidis D, Tornillo L, Terracciano L, Ng CKY, Piscuoglio S, von Flüe M, Spagnoli G, Eppenberger-Castori S, Iezzi G, Droeser RA. Infiltration by IL22-Producing T Cells Promotes Neutrophil Recruitment and Predicts Favorable Clinical Outcome in Human Colorectal Cancer. Cancer Immunol Res. 2020 Aug 24. doi: 10.1158/2326-6066.CIR-19-0934.
Manfredonia C, Muraro MG, Hirt C, Mele V, Governa V, Papadimitropoulos A, Däster S, Soysal SD, Droeser RA, Mechera R, Oertli D, Rosso R, Bolli M, Zettl A, Terracciano LM, Spagnoli GC, Martin I, Iezzi G. Maintenance of Primary Human Colorectal Cancer Microenvironment Using a Perfusion Bioreactor-Based 3D Culture System. Adv Biosyst. 2019 Apr;3(4):e1800300. doi: 10.1002/adbi.201800300.
Iezzi G, Cremonesi E, Majno PE. Pro-tumoral role of gut bacteria: sabotaging immune cell recruitment. Ann Transl Med. 2019 Feb;7(3):59. doi: 10.21037/atm.2018.12.56.
Cremonesi E, Governa V, Garzon JFG, Mele V, Amicarella F, Muraro MG, Trella E, Galati-Fournier V, Oertli D, Däster SR, Droeser RA, Weixler B, Bolli M, Rosso R, Nitsche U, Khanna N, Egli A, Keck S, Slotta-Huspenina J, Terracciano LM, Zajac P, Spagnoli GC, Eppenberger-Castori S, Janssen KP, Borsig L, Iezzi G. Gut microbiota modulate T cell trafficking into human colorectal cancer. Gut. 2018 Nov;67(11):1984-1994. doi: 10.1136/gutjnl-2016-313498. Epub 2018 Feb 6. Artikel on Youtube
Persons involved in the project
PD Dr. Giandomenica Iezzi
Head of Translational Research Lab, Università della Svizzera Italiana, Department of Surgery, Ente Ospedaliero Cantonale and Faculty of Biomedical ScienceProf. Majno-Hurst
, Head of the Department of Surgery, Ente Ospedaliero Cantonale Lugano and Chair of Surgery of the Università Svizzera Italiana (USI) Prof. Dimitri Christoforidis
, Deputy Head of the Department of Surgery Ente Ospedaliero Cantonale Lugano, specialized in colorectal surgery
Last update to this project presentation 22.09.2022