Human CD141+dendritic cells (cDC1) are impaired in advanced melanoma patients but can be targeted to increase efficacy of anti-PD-1 checkpoint inhibitor therapy

Dendritic cells (DCs) as professional antigen-presenting cells with unique T-cell stimulatory capacity represent a potential means by which to improve response rates towards immune checkpoint inhibitor antibodies (ICIs) such as anti-PD-1 (pembrolizumab) in melanoma. The conventional type 1 DC subset (cDC1) is indispensable for the efficacy of ICIs in animal models; however, very little is known about the role of cDC1 in human cancer patients. To address this, we developed a whole-blood assay for quantifying and characterizing human DC subsets (cDC1, cDC2 and plasmacytoid DCs [pDCs]) by flow cytometry and compared these in healthy donors and stage III and IV metastatic melanoma patients. cDC1 and pDC numbers were significantly reduced in stage IV melanoma patients compared to healthy controls. Moreover, cDC1s in melanoma patients were selectively impaired in their ability to upregulate CD83 expression after stimulation with TLR3 and TLR7/8 agonists ex vivo. Although DC numbers did not correlate with responses to anti-PD-1 and/or anti-CTLA-4 ICIs, their numbers and capacity to upregulate CD83 declined further during treatment in nonresponding patients. To examine whether harnessing cDC1 could improve responses to ICIs in human melanoma, we developed a humanized mouse model by engrafting immunodeficient NSG-SGM3 mice with CD34+ hematopoietic stem cells from umbilical cord blood followed by transplantation of a human melanoma cell line. Treatment with anti-PD-1 in this model was ineffective at controlling tumor growth, but efficacy was enhanced by indirectly expanding and activating DCs in vivo with Flt-3 ligand (Flt3L) and TLR3 agonist polyI:C. Moreover, intratumoral injection of cDC1s, but not cDC2s, resulted in reduced tumor growth when combined with anti-PD-1 treatment. Together, these data illustrate impairments in cDC1 in advanced melanoma patients and provide rationale for harnessing them to increase immunogenicity and response rates to ICIs. Citation Format: Liam O’Brien, Yoke Seng Lee, Carina Walpole, Ingrid Leal Rojas, Kelly-Anne Masterman, Victoria Atkinson, Andrew Barbour, Kristen Radford. Human CD141+ dendritic cells (cDC1) are impaired in advanced melanoma patients but can be targeted to increase efficacy of anti-PD-1 checkpoint inhibitor therapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B42.