Poster Presentation 18th International Symposium on Dendritic Cells 2026

Regulating myeloid cells to promote mature tertiary lymphoid structures and enhance anti-tumor immunity (#275)

Elizabeth E Evans 1 , Crystal Mallow 1 , Holm Bussler 1 , Terrence L Fisher 1 , Maria Scrivens 1 , Ayana T Ruffin 2 , Elaine Gersz 1 , Renee Kirk 1 , Malgorzata Gil-Moore 1 , Saurabh Garg 3 , Colin Snyder 3 , Ellen Giampoli 4 , Brian Czerniecki 3 , Michael C Lowe 2 , Conor Steuer 2 , Nabil Saba 2 , Gregory B Lesinski 2 , Chrystal M Paulos 2 , Maurice Zauderer 1
  1. Vaccinex, Rochester, NY, United States
  2. Winship Cancer Center of Emory University, Atlanta, Georgia, USA
  3. H. Lee Moffitt Cancer Center, Tampa, Florida, USA
  4. University of Rochester, Rochester, NY, United States

Strategies to recruit and activate DC have the potential to enhance cancer immunotherapy. Semaphorin4D (SEMA4D) binding to PLXNB1/B2 receptors on myeloid cells drives immune exclusion and myeloid suppression. Pepinemab, SEMA4D-blocking antibody, reprogrammed myeloid contexture and promoted activated APC and T cells in the TME in preclinical and clinical studies.

In two separate neoadjuvant studies of surgically resectable metastatic melanoma (NCT03769155) and HNSCC (NCT03690986), treatment with immune checkpoint inhibitors (ICI), nivolumab and/or ipilimumab, and combinations with pepinemab were employed to investigate effects on tumor immunity. Tumor biopsies at screening and on-treatment were characterized using multiplex immunohistochemistry, RNAseq and spatial transcriptomics. In patients receiving pepinemab-containing combinations, TME demonstrated increased density of cDC1 and improved ratio of activated HLA-DR+ to suppressive myeloid cells, compared to ICI alone. Lymphoid aggregates (LA) were larger and more mature, containing follicular CD21+ DC and CD23+ B cells, and CXCR5+ Tfh cells characteristic of germinal centers. Spatial transcriptomics of mLA revealed more clonal, less diverse TCR repertoires, and significant changes in genes associated with antigen presentation and follicular organization. Mature LA were associated with clinical benefit. Tumor expression of FLT3-associated genes and circulating FLT3L protein, both linked to cDC1 and TLS development and function, were elevated in patients receiving pepinemab-containing therapy.

We hypothesized that effects of pepinemab could be further enhanced by increasing the DC available in the TME. In preclinical studies,  ex vivo-expanded DC-1 via intratumoral injection with systemic administration of SEMA4D-blocking antibody resulted in improved DC trafficking to lymph nodes and remarkable regression of target and distant tumors. Extending this approach to induce in vivo expansion of DC with Flt3L combined with SEMA4D-blocking antibody induced regression of established tumors, particularly in ICI-resistant models.

Collectively, these findings suggest that pepinemab’s myeloid-remodeling effects may help overcome barriers imposed by suppressive myeloid populations and impaired antigen presentation in TME.