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

Aleksandar Murgaski, Mate Kiss, Helena Van Damme, Daliya Kancheva, Isaure Vanmeerbeek, Jiri Keirsse, Eva Hadadi, Jan Brughmans, Sana M. 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

Onderzoeksoutput: Articlepeer review

15 Citaten (Scopus)
64 Downloads (Pure)

Samenvatting

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.
Originele taal-2English
Pagina's (van-tot)3785-3801
Aantal pagina's17
TijdschriftCancer Research
Volume82
Nummer van het tijdschrift20
DOI's
StatusPublished - 15 okt. 2022

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

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