PORTEFEUILLE

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 recently been 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 microbiota, have the ability to stimulate tumor cells to produce chemotactic factors capable of attracting immune cells into tumor tissues. Upon analysis of gut microbiota composition in 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 a high therapeutic potential of the administration of identified bacteria to increase CRC infiltration by immune cells, thereby improving clinical outcome. With the present project, we aimed to select the most effective bacterial species and combinations for subsequent clinical application.

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, it might increase response rates to standard chemotherapies or emerging immunotherapies.

The project has been 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. During the funding period, we have investigated the capacity of bacterial species, previously found to be associated with CRC infiltration by immune cells, to induce in tumor cells the expression of immune cell-recruiting chemokines. We have identified a group of five bacterial species effectively inducing in tumor cells upregulation of chemokine genes in vitro. Then, by using experimental CRC models, we have tested the ability of the two most effective bacterial species to promote recruitment of immune cells into MMR-proficient and -deficient CRCs. We found that in MMR-deficient tumors, characterized by a high mutational burden, administration of one of the tested bacteria, defined as OTU8, was per se sufficient to lead to reduced tumor growth. Instead, in MMR-proficient tumors, characterized by low mutational burden, poor immune infiltration and unresponsiveness to immunotherapies based on immunological checkpoint inhibition (ICI), OTU8 administration did not lead per se to significant reduction of tumor growth, but promoted intra-tumoral T cell recruitment and enhanced ICI effectiveness. These findings provide a rationale for the administration of the identified bacteria in order to increase responsiveness to ICI-based immunotherapy, and might lead to an extension of clinical indications for ICI beyond MMR-deficient tumors.

Mele V, Mele V, Basso C, Governa V, Glaus Garzon JF, Muraro MG, Däster S, Nebiker CA, Mechera R, Bolli M, Schmidt A, Geiger R, Spagnoli GC, Christoforidis D, Majno PE, Borsig L, Iezzi G. Identification of TPM2 and CNN1 as Novel Prognostic Markers in Functionally Characterized Human Colon Cancer-Associated Stromal Cells. Cancers (Basel). 2022 Apr 16;14(8):2024. doi: 10.3390/cancers14082024.
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

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