Ana Montalban-Arques, Egle Katkeviciute, Philipp Busenhart, Anna Bircher, Jakob Wirbel, Georg Zeller, Yasser Morsy, Lubor Borsig, Jesus F. Glaus Garzon, Anne Müller, Isabelle C. Arnold, Mariela Artola-Boran, Michael Krauthammer, Anna Sintsova, Nicola Zamboni, Gabriel E. Leventhal, Laura Berchtold, Tomas de Wouters, Gerhard Rogler, Katharina Baebler, Marlene Schwarzfischer, Larissa Hering, Ivan Olivares-Rivas, Kirstin Atrott, Claudia Gottier, Silvia Lang, Onur Boyman, Ralph Fritsch, Markus G. Manz, Marianne R. Spalinger, Michael Scharl
Cell Host Microbe. 2021 Aug 25; S1931-3128(21)00377-2.
Despite overall success, T cell checkpoint inhibitors for cancer treatment are still only efficient in aminority of patients. Recently, intestinal microbiota was found to critically modulate anti-cancer immunity and therapy response. Here, we identify Clostridiales members of the gut microbiota associated with a lower tumor burden in mouse models of colorectal cancer (CRC). Interestingly, these commensal species are also significantly reduced in CRC patients compared with healthy controls. Oral application of a mix of four Clostridiales strains (CC4) in mice prevented and even successfully treated CRC as stand-alone therapy. This effect depended on intratumoral infiltration and activation of CD8+ T cells. Single application of Roseburia intestinalis or Anaerostipes caccae was even more effective than CC4. In a direct comparison, the CC4 mix supplementation outperformed anti-PD-1 therapy in mouse models of CRC and melanoma. Our findings provide a strong preclinical foundation for exploring gut bacteria as novel stand-alone therapy against solid tumors.
Egle Katkeviciute , Larissa Hering , Ana Montalban-Arques , Philipp Busenhart , Marlene Schwarzfischer , Roberto Manzini , Javier Conde , Kirstin Atrott , Silvia Lang , Gerhard Rogler, Elisabeth Naschberger , Vera S Schellerer, Michael Stürzl , Andreas Rickenbacher , Matthias Turina , Achim Weber , Sebastian Leibl , Gabriel E Leventhal , Mitchell Levesque, Onur Boyman, Michael Scharl, Marianne R Spalinger
J Clin Invest. 2021 Jan 4;131(1):e140281
Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) recently emerged as a promising cancer immunotherapy target. We set out to investigate the functional role of PTPN2 in the pathogenesis of human colorectal carcinoma (CRC), as its role in immune-silent solid tumors is poorly understood. We demonstrate that in human CRC, increased PTPN2 expression and activity correlated with disease progression and decreased immune responses in tumor tissues. In particular, stage II and III tumors displayed enhanced PTPN2 protein expression in tumor-infiltrating T cells, and increased PTPN2 levels negatively correlated with expression of PD-1, CTLA4, STAT1, and granzyme A. In vivo, T cell- and DC-specific PTPN2 deletion reduced tumor burden in several CRC models by promoting CD44+ effector/memory T cells, as well as CD8+ T cell infiltration and cytotoxicity in the tumor. In direct relevance to CRC treatment, T cell-specific PTPN2 deletion potentiated anti-PD-1 efficacy and induced antitumor memory formation upon tumor rechallenge in vivo. Our data suggest a role for PTPN2 in suppressing antitumor immunity and promoting tumor development in patients with CRC. Our in vivo results identify PTPN2 as a key player in controlling the immunogenicity of CRC, with the strong potential to be exploited for cancer immunotherapy.
Marianne R Spalinger, Thomas Sb Schmidt, Marlene Schwarzfischer, Larissa Hering, Kirstin Atrott, Silvia Lang, Claudia Gottier, Annelies Geirnaert, Christophe Lacroix , Xuezhi Dai , David J Rawlings , Andrew C Chan , Christian von Mering, Gerhard Rogler, Michael Scharl
J Clin Invest. 2019 May 20;129(6):2527-2541.
The gut microbiota is crucial for our health, and well-balanced interactions between the host's immune system and the microbiota are essential to prevent chronic intestinal inflammation, as observed in inflammatory bowel diseases (IBD). A variant in protein tyrosine phosphatase non-receptor type 22 (PTPN22) is associated with reduced risk of developing IBD, but promotes the onset of autoimmune disorders. While the role of PTPN22 in modulating molecular pathways involved in IBD pathogenesis is well studied, its impact on shaping the intestinal microbiota has not been addressed in depth. Here, we demonstrate that mice carrying the PTPN22 variant (619W mice) were protected from acute dextran sulfate sodium (DSS) colitis, but suffered from pronounced inflammation upon chronic DSS treatment. The basal microbiota composition was distinct between genotypes, and DSS-induced dysbiosis was milder in 619W mice than in WT littermates. Transfer of microbiota from 619W mice after the first DSS cycle into treatment-naive 619W mice promoted colitis, indicating that changes in microbial composition enhanced chronic colitis in those animals. This indicates that presence of the PTPN22 variant affects intestinal inflammation by modulating the host's response to the intestinal microbiota.
Spalinger MR, Kasper S, Gottier C, Lang S, Atrott K, Vavricka SR, Scharl S, Raselli T, Frey-Wagner I, Gutte PM, Grütter MG, Beer HD, Contassot E, Chan AC, Dai X, Rawlings DJ, Mair F, Becher B, Falk W, Fried M, Rogler G, Scharl M
J Clin Invest. 2016 May 2;126(5):1783-800.
Inflammasomes form as the result of the intracellular presence of danger-associated molecular patterns and mediate the release of active IL-1β, which influences a variety of inflammatory responses. Excessive inflammasome activation results in severe inflammatory conditions, but physiological IL-1β secretion is necessary for intestinal homeostasis. Here, we have described a mechanism of NLRP3 inflammasome regulation by tyrosine phosphorylation of NLRP3 at Tyr861. We demonstrated that protein tyrosine phosphatase non-receptor 22 (PTPN22), variants in which are associated with chronic inflammatory disorders, dephosphorylates NLRP3 upon inflammasome induction, allowing efficient NLRP3 activation and subsequent IL-1β release. In murine models, PTPN22 deficiency resulted in pronounced colitis, increased NLRP3 phosphorylation, but reduced levels of mature IL-1β. Conversely, patients with inflammatory bowel disease (IBD) that carried an autoimmunity-associated PTPN22 variant had increased IL-1β levels. Together, our results identify tyrosine phosphorylation as an important regulatory mechanism for NLRP3 that prevents aberrant inflammasome activation.
Congratulations to Dr. Ana Montalban-Arques for winning the 1st prize in the Emerging Talents category of Falling Walls Meeting in Berlin
Sendung zum Thema: «Unterschätztes Mikrobiom – gesunder Darm, gesunder Mensch?"
Artikel zum Thema: "Ernährung als Medizin - Darmbakterien sollen Krebs beseitigen"