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Influence of intestinal microbial metabolites on the abscopal effect after radiation therapy combined with immune checkpoint inhibitors.
Clin. Transl. Radiat. Oncol. 46:100758 (2024)
BACKGROUND: Most clinical studies failed to elicit a strong antitumor immune response and subsequent systemic tumor regression after radiation therapy (RT), even in combination with the immune checkpoint inhibitors (ICI) anti-CTLA4 or anti-PD1. Mechanistically, type I interferon (IFN-I) activation is essential for the development of such abscopal effects (AE); however, mechanisms driving or limiting IFN-I activation are ill defined. Groundbreaking discoveries have shown that antibiotics (ABx) can affect oncological outcomes and that microbiota-derived metabolites can modulate systemic antitumor immunity. Recent studies have demonstrated that the bacterial metabolites desaminotyrosine (DAT) and indole-3-carboxaldehyde (ICA) can enhance IFN-I activation in models of inflammatory diseases. MATERIALS AND METHODS: The subcutaneous bilateral MC38 tumor model is a widely used experimental tool to study the AE in mice. We applied it to explore the influence of broad-spectrum ABx, DAT and ICA on the AE after radioimmunotherapy (RIT). We performed 1x8 Gy of the primary tumor ± anti-CTLA4 or anti-PD1, and ± daily oral application of ABx or metabolites. RESULT: Combinatory ABx had neither a significant effect on tumor growth of the irradiated tumor nor on tumor progression of the abscopal tumor after RIT with anti-CTLA4. Furthermore, DAT and ICA did not significantly impact on the AE after RIT with anti-CTLA4 or anti-PD1. Surprisingly, ICA even appears to reduce outcomes after RIT with anti-CTLA4. CONCLUSION: We did not find a significant impact of combinatory ABx on the AE. Experimental application of the IFN-I-inducing metabolites DAT or ICA did not boost the AE after combined RIT. Additional studies are important to further investigate whether the intestinal microbiota or specific microbiota-derived metabolites modulate the AE.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Abscopal Effect ; Bacterial Metabolites ; Immune Checkpoint Inhibition ; Intestinal Microbiota ; Type I Interferon; Immunotherapy
ISSN (print) / ISBN
2405-6308
e-ISSN
2405-6308
Zeitschrift
Clinical and translational radiation oncology
Quellenangaben
Band: 46,
Artikelnummer: 100758
Verlag
Elsevier
Verlagsort
Amsterdam
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Radiation Medicine (IRM)
Förderungen
Friedrich Naumann Foundation for Freedom
Else Kroner-Forschungskolleg of the Technical University of Munich
German Cancer Aid
Else Kroner-Fresenius-Stiftung
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)
TUM School of Medicine and Health
Else Kroner-Forschungskolleg of the Technical University of Munich
German Cancer Aid
Else Kroner-Fresenius-Stiftung
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)
TUM School of Medicine and Health