| First Author | Murgaski A | Year | 2022 |
| Journal | Cancer Res | Volume | 82 |
| Issue | 20 | Pages | 3785-3801 |
| PubMed ID | 35979635 | Mgi Jnum | J:336729 |
| Mgi Id | MGI:7356431 | Doi | 10.1158/0008-5472.CAN-22-0094 |
| Citation | Murgaski A, et al. (2022) Efficacy of CD40 Agonists Is Mediated by Distinct cDC Subsets and Subverted by Suppressive Macrophages. Cancer Res 82(20):3785-3801 |
| abstractText | Agonistic alphaCD40 therapy has been shown to inhibit cancer progression in only a fraction of patients. Understanding the cancer cell-intrinsic and microenvironmental determinants of alphaCD40 therapy response is therefore crucial to identify responsive patient populations and to design efficient combinatorial treatments. Here, we show that the therapeutic efficacy of alphaCD40 in subcutaneous melanoma relies on preexisting, type 1 classical dendritic cell (cDC1)-primed CD8+ T cells. However, after administration of alphaCD40, cDC1s were dispensable for antitumor efficacy. Instead, the abundance of activated cDCs, potentially derived from cDC2 cells, increased and further activated antitumor CD8+ T cells. Hence, distinct cDC subsets contributed to the induction of alphaCD40 responses. In contrast, lung carcinomas, characterized by a high abundance of macrophages, were resistant to alphaCD40 therapy. Combining alphaCD40 therapy with macrophage depletion led to tumor growth inhibition only in the presence of strong neoantigens. Accordingly, treatment with immunogenic cell death-inducing chemotherapy sensitized lung tumors to alphaCD40 therapy in subcutaneous and orthotopic settings. These insights into the microenvironmental regulators of response to alphaCD40 suggest that different tumor types would benefit from different combinations of therapies to optimize the clinical application of CD40 agonists. SIGNIFICANCE: This work highlights the temporal roles of different dendritic cell subsets in promoting CD8+ T-cell-driven responses to CD40 agonist therapy in cancer. |
