Lee and O’Brien et al. investigated the number and function of human CD141+ conventional type 1 dendritic cells (CD141+ DCs) in advanced (Stage 3 and 4) metastatic melanoma patients. Blood CD141+ DCs numbers were decreased in stage 4 patients, expressed lower HLA-DR and CD83 levels when activated ex vivo, and continued to decrease in non-responding patients over 6 months of treatment, compared to healthy controls. In a humanized melanoma mouse model, anti-PD-1 monotherapy was ineffective, but was significantly enhanced by either expanding and activating DCs with Flt3L and polyIC, or by i.t. injections of CD141+ DCs.
Contributed by Katherine Turner
BACKGROUND: The conventional type 1 dendritic cell subset (cDC1) is indispensable for tumor immune responses and the efficacy of immune checkpoint inhibitor (ICI) therapies in animal models but little is known about the role of the human CD141(+) DC cDC1 equivalent in patients with melanoma. METHODS: We developed a flow cytometry assay to quantify and characterize human blood DC subsets in healthy donors and patients with stage 3 and stage 4 metastatic melanoma. To examine whether harnessing CD141(+) DCs could improve responses to ICIs in human melanoma, we developed a humanized mouse model by engrafting immunodeficient NSG-SGM3 mice with human CD34(+) hematopoietic stem cells (HSCs) from umbilical cord blood followed by transplantation of a human melanoma cell line and treatment with anti-programmed cell death protein-1 (anti-PD-1). RESULTS: Blood CD141(+) DC numbers were significantly reduced in patients with stage 4 melanoma compared with healthy controls. Moreover, CD141(+) DCs in patients with melanoma were selectively impaired in their ability to upregulate CD83 expression after stimulation with toll-like receptor 3 (TLR3) and TLR7/8 agonists ex vivo. Although DC numbers did not correlate with responses to anti-PD-1 and/or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) ICIs, their numbers and capacity to upregulate CD83 declined further during treatment in non-responding patients. Treatment with anti-PD-1 was ineffective at controlling tumor growth in humanized mice but efficacy was enhanced by indirectly expanding and activating DCs in vivo with fms-like tyrosine kinase-3 ligand (Flt3L) and a TLR3 agonist. Moreover, intratumoral injections of CD141(+) DCs resulted in reduced tumor growth when combined with anti-PD-1 treatment. CONCLUSIONS: These data illustrate quantitative and qualitative impairments in circulating CD141(+) DCs in patients with advanced melanoma and that increasing CD141(+) DC number and function is an attractive strategy to enhance immunogenicity and response rates to ICIs.
Author Info: (1) Mater Research, The University of Queensland, Woolloongabba, Queensland, Australia. (2) Mater Research, The University of Queensland, Woolloongabba, Queensland, Australia. (3)
Author Info: (1) Mater Research, The University of Queensland, Woolloongabba, Queensland, Australia. (2) Mater Research, The University of Queensland, Woolloongabba, Queensland, Australia. (3) Mater Research, The University of Queensland, Woolloongabba, Queensland, Australia. (4) Mater Research, The University of Queensland, Woolloongabba, Queensland, Australia. (5) Mater Research, The University of Queensland, Woolloongabba, Queensland, Australia. (6) Mater Research, The University of Queensland, Woolloongabba, Queensland, Australia. (7) Princess Alexandra Hospital Clinical School, The University of Queensland, Woolloongabba, Queensland, Australia. (8) Princess Alexandra Hospital Clinical School, The University of Queensland, Woolloongabba, Queensland, Australia. (9) Mater Research, The University of Queensland, Woolloongabba, Queensland, Australia kristen.radford@mater.uq.edu.au.
