American Association for Cancer Research
Browse
crc-23-0550_fig4.png (685.54 kB)

FIGURE 4 from Neoadjuvant CD40 Agonism Remodels the Tumor Immune Microenvironment in Locally Advanced Esophageal/Gastroesophageal Junction Cancer

Download (685.54 kB)
figure
posted on 2024-01-25, 14:20 authored by Maira Soto, Erin L. Filbert, Hai Yang, Stephanie Starzinski, Alec Starzinski, Marissa Gin, Brandon Chen, Phi Le, Tony Li, Brandon Bol, Alexander Cheung, Li Zhang, Frank J. Hsu, Andrew Ko, Lawrence Fong, Bridget P. Keenan

Sotigalimab induces activation and trafficking of immune cells within the blood. A and B, Heat maps of cell frequency and cell surface marker expression as analyzed by CyTOF for T and NK cells (A) and antigen-presenting cells (B; pre n = 6, post n = 6). The count column shows the number of cells in each cluster. The “frequency signif” columns indicates statistical significance for differences in cell frequency of which there were none. Red and blue in the protein columns indicate significant up- or down-regulation of expression for the indicated cell cluster. C, UMAP plots of PBMCs analyzed by CITEseq showing cell annotation (top) and abundance of cells by timepoint (bottom; pre n = 6, post n = 6). D, Quantification of cell frequency as percentage of all immune cells by timepoint from the CITEseq data (pre n = 6, post n = 6). *, P < 0.05; **, P < 0.01, unmarked comparisons are not significant. E, Expression of cell surface proteins indicative of cell trafficking and activation via CITEseq for CD8+ and CD4+ T cells, and adhesion molecules in CD14+ monocytes, for pre- and post-sotigalimab (pre n = 6, post n = 6). For scRNAseq data in E, all comparisons are significant with an adjusted P < 0.05.

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)

History

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.