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Felchle, H.* ; Gissibl, J.* ; Lansink Rotgerink, L.* ; Nefzger, S.M.* ; Walther, C.N.* ; Timnik, V.R.* ; Combs, S.E. ; Fischer, J.C.*

Influence of intestinal microbial metabolites on the abscopal effect after radiation therapy combined with immune checkpoint inhibitors.

Clin. Transl. Radiat. Oncol. 46:100758 (2024)

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Open Access Gold as soon as Publ. Version/Full Text is submitted to ZB.

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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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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Abscopal Effect ; Bacterial Metabolites ; Immune Checkpoint Inhibition ; Intestinal Microbiota ; Type I Interferon; Immunotherapy

ISSN (print) / ISBN 2405-6308

e-ISSN 2405-6308

Journal Clinical and translational radiation oncology

Quellenangaben Volume: 46, Article Number: 100758

Publisher Elsevier

Publishing Place Amsterdam

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Radiation Medicine (IRM)

Grants 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