Tumor-infiltrating myeloid cells are activated post-sotigalimab with alterations in antigen processing and metabolic pathways. A, MIBI analysis depicts changes in cell density and upregulation of activation markers for DCs in the TME (representative image: patient 04). B, Quantification of DC density in the tumor pre- and post-sotigalimab by total DCs and specific subset (pre n = 5, post n = 4). C, Quantification of activation markers CD86, HLA-II, and CD40 expression pre- and post-sotigalimab by MIBI for all DCs pre- and post-treatment (pre n = 5, post n = 4). D and E, Visualization (D) and quantification (E) of monocyte, macrophage, and MDSC subsets using MIBI (representative image: patient 04; pre n = 5, post n = 4). F, The top pathways either up or downregulated post-sotigalimab in monocytes/macrophages and DCs, from scRNAseq analysis, are shown as a heat map (pre n = 3, post n = 4). The proportion of enriched genes within the pathway is shown within each box. Gray color corresponds to no enriched genes within the pathway. G, Individual cells were scored for genes involved in oxidative phosphorylation (y-axis) and genes related to antigen processing and presentation for monocytes/macrophages and DCs pre- and post-sotigalimab (x-axis) (pre n = 3, post n = 4). All statistical changes for MIBI data were measured by t test. *, P ≤ 0.05; **, P ≤ 0.01.
Funding
HHS | NIH | National Cancer Institute (NCI)
Apexigen America, Inc.
UC | UCSF | Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (HDFCCC, UCSF)
HHS | NIH | U.S. National Library of Medicine (NLM)
ARTICLE ABSTRACT
Sotigalimab is an agonistic anti-CD40 mAb that can modulate antitumor immune responses. In a phase II clinical trial of sotigalimab combined with neoadjuvant chemoradiation (CRT) in locally advanced esophageal/gastroesophageal junction (E/GEJ) cancer with the primary outcome of efficacy as measured by pathologic complete response (pCR) rate, the combination induced pCR in 38% of treated patients. We investigated the mechanism of action of sotigalimab in samples obtained from this clinical trial. Tumor biopsies and peripheral blood samples were collected at baseline, following an initial dose of sotigalimab, and at the time of surgery after CRT completion from six patients. High dimensional single-cell techniques were used, including combined single-cell RNA-sequencing and proteomics (CITEseq) and multiplexed ion beam imaging, to analyze immune responses. Sotigalimab dramatically remodeled the immune compartment in the periphery and within the tumor microenvironment (TME), increasing expression of molecules related to antigen processing and presentation and altering metabolic pathways in myeloid cells. Concomitant with these changes in myeloid cells, sotigalimab treatment primed new T cell clonotypes and increased the density and activation of T cells with enhanced cytotoxic function. Sotigalimab treatment also induced a decrease in the frequency of Tregs in the TME. These findings indicate that a single dose of sotigalimab leads to enhanced antigen presentation that can activate T cells and induce new T cell clones. This restructuring of the TME provides elements which are critical to the development of effective antitumor immune responses and improved clinical outcomes.
