Efficacy of CD40 agonists is mediated by distinct cDC subsets and subverted by suppressive macrophages

Aleksandar Murgaski, Máté Kiss, Helena Van Damme, Daliya Kancheva, Isaure Vanmeerbeerk, Jiri Keirsse, Eva Hadadi, Jan Brughmans, Sana Arnouk, Ahmed E. I. Hamouda, Ayla Debraekeleer, Victor Bosteels, Yvon Elkrim, Louis Boon, Sabine Hoves, Niels Vandamme, Sofie Deschoemaeker, Sophie Janssens, Abhishek D Garg, Greetje Vande VeldeMartina Schmittnaegel, Carola H Ries, Damya Laoui

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Abstract

Agonistic αCD40 therapy has been shown to inhibit cancer progression in only a fraction of patients. Understanding the cancer cell-intrinsic and microenvironmental determinants of αCD40 therapy response is therefore crucial to identify responsive patient populations and design efficient combinatorial treatments. Here, we show that the therapeutic efficacy of αCD40 in subcutaneous melanoma relies on pre-existing, type 1 classical dendritic cell (cDC1)-primed CD8+ T cells. However, after administration of αCD40, cDC1s were dispensable for anti-tumour efficacy. Instead, the abundance of activated cDCs, potentially derived from cDC2 cells, increased and further activated antitumour CD8+ T cells. Hence, distinct cDC subsets contributed to the induction of αCD40 responses. By contrast, lung carcinomas, characterized by a high abundance of macrophages, were resistant to αCD40 therapy. Combining αCD40 therapy with macrophage depletion led to tumour growth inhibition only in the presence of strong neoantigens. Accordingly, treatment with immunogenic cell death-inducing chemotherapy sensitized lung tumours to αCD40 therapy in subcutaneous and orthotopic settings. These insights into the microenvironmental regulators of response to αCD40 suggest that different tumour types would benefit from different combinations of therapies to optimize the clinical application of CD40 agonists.
Original languageEnglish
Pages (from-to)3785-3801
Number of pages17
JournalCancer Research
Volume82
Issue number20
DOIs
Publication statusPublished - 15 Oct 2022

Bibliographical note

Funding Information:
A. Murgaski reports grants from Fonds Wetenschappelijk Onderzoek (FWO) and Kom op tegen Kanker (KOTK) during the conduct of the study. E. Hadadi reports grants from Research Foundation Flanders (FWO) during the conduct of the study. S. Hoves reports a patent 20200392234 pending, a patent 20190284284 pending, a patent 20180346581 pending, a patent 20170051065 pending, a patent 20160220669 pending, a patent 9192667 issued, a patent 20150073129 pending, and a patent 20140314771 pending; and also reports employment with Roche Diagnostics GmbH and ownership of Hoffmann La Roche stock. S. Deschoemaeker reports grants from Stichting tegen Kanker post-doctoraal mandaat (2021-023) during the conduct of the study. M. Schmittnaegel reports employment with Roche Diagnostics GmbH. C.H. Ries reports personal fees from Roche during the conduct of the study; personal fees from Macomics Ltd. and Dr. Carola Ries Consulting outside the submitted work; also has a patent for EP12158519 issued. D. Laoui reports other support from Roche and grants from FWO, VUB, and Collen-Francqui Foundation during the conduct of the study. No disclosures were reported by the other authors.

Funding Information:
assistance. They thank Pascal Merchiers, Akiko Iwasaki, and Orr-El Weizman for providing reagents. The authors thank the VIB singularity platform for support and access to scRNA-seq technologies and Ria Roelandt for the library preparations. They thank Mika€el Pittet, Patrick De Baetselier, Jo Van Ginderachter, and Kiavash Movahedi for insightful discussions. A. Murgaski, H. Van Damme, I. Vanmeerbeek, and S.M. Arnouk are supported by an FWO doctoral fellowship (1S16718N, 1S24117N, 1S06821N, and 1S78120N). S. Janssens and V. Bosteels are funded by an EOS grant (G0G7318N) and FWO predoctoral fellowship. A.D. Garg was supported by FWO (G0B4620N; EOS grant 30837538), KU Leuven, Kom op Tegen Kanker, and VLIR-UOS. G. Vande Velde was supported by KU Leuven Internal Funds (C24/17/061 and STG/15/024). D. Laoui was supported by grants from FWO (12Z1820N), Kom op Tegen Kanker, Stichting tegen kanker, and Vrije Universiteit Brussel.

Publisher Copyright:
© 2022 American Association for Cancer Research Inc.. All rights reserved.

Copyright:
Copyright 2022 Elsevier B.V., All rights reserved.

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