Distinct cDC subsets co-operate in CD40 agonist response while suppressive microenvironments and lack of antigens subvert efficacy

Agonistic αCD40 therapy has shown to inhibit cancer progression, but only in a fraction of patients. Hence, understanding the cancer cell-intrinsic and microenvironmental determinants of αCD40 therapy response is crucial to identify responsive patient populations and design efficient combination treatments. Here, we showed that the therapeutic efficacy of αCD40 in responder melanoma tumours, relied on pre-existing cDC1-primed CD8+ T cells, however cDC1s were dispensable after αCD40 administration. Surprisingly, in response to αCD40 the abundance of activated cDCs, potentially derived from cDC2s increased, thereby further activating antitumour CD8+ T cells. Hence, distinct cDC subsets are required to induce αCD40 responses. By contrast, lung tumours, characterised 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 sensitised non-immunogenic tumours to αCD40 therapy. ### Competing Interest Statement C.H. R., M.S., and S.H., are current or former Roche employees. S.H. and C.H.R. hold granted or pending patent applications pertaining to emactuzumab and its combinations. S.H. holds Roche shares. C.H.R. consults for Verseau Therapeutics, Ridgeline Therapeutics, and iOmx Therapeutics AG.