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TIM4 expression by dendritic cells mediates uptake of tumor-associated antigens and anti-tumor responses

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Nicoletta Caronni, Giulia Maria Piperno, Francesca Simoncello, Oriana Romano, Simone Vodret, Yuichi Yanagihashi, Regine Dress, Charles Antoine Dutertre, Mattia Bugatti, Pierre Bourdeley, Annalisa Del Prete, Tiziana Schioppa, Emilia Maria Cristina Mazza, Licio Collavin, Serena Zacchigna, Renato Ostuni, Pierre Guermonprez, William Vermi, Florent Ginhoux, Silvio Bicciato & 2 more Shigekatzu Nagata, Federica Benvenuti

Original languageEnglish
Article number2237
JournalNature Communications
Volume12
Issue number1
DOIs
PublishedDec 2021

Bibliographical note

Funding Information: This work was supported by AIRC IG (14414 and 21636) to F.B. N.C. was supported by AIRC and ICGEB fellowship. F.S. is supported by an ICGEB fellowship. G.M.P. is supported by AIRC grant (21636) to F.B. Y.Y. and S.N. were supported by Grant-in-Aid for Scientific Research (S) for the Promotion of Science 15H05785 from the Japan Society for the Promotion of Science (JSPS) (to S.N.). S.B. was supported by AIRC Special Program Molecular Clinical Oncology “5 per mille” (Grant no. 10016 and grant n. 22759) and Italian Epigenomics Flagship Project (Epigen). O.R. is supported by Fon-dazione Umberto Veronesi (Post-Doctoral Fellowship 2020). We thank Debora Brescia supported by Fondazione Beretta (Brescia, Italy) for technical support. We thank Roberto Amadio and Luciano Gaston-Morosi for help with data analysis and statistics. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

Abstract

Acquisition of cell-associated tumor antigens by type 1 dendritic cells (cDC1) is essential to induce and sustain tumor specific CD8+ T cells via cross-presentation. Here we show that capture and engulfment of cell associated antigens by tissue resident lung cDC1 is inhibited during progression of mouse lung tumors. Mechanistically, loss of phagocytosis is linked to tumor-mediated downregulation of the phosphatidylserine receptor TIM4, that is highly expressed in normal lung resident cDC1. TIM4 receptor blockade and conditional cDC1 deletion impair activation of tumor specific CD8+ T cells and promote tumor progression. In human lung adenocarcinomas, TIM4 transcripts increase the prognostic value of a cDC1 signature and predict responses to PD-1 treatment. Thus, TIM4 on lung resident cDC1 contributes to immune surveillance and its expression is suppressed in advanced tumors.

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