CD137 agonism enhances anti-PD1 induced activation of expanded CD8+ T cell clones in a neoadjuvant pancreatic cancer clinical trial
Successful pancreatic ductal adenocarcinoma (PDAC) immunotherapy requires therapeutic combinations that induce quality T cells. Tumor microenvironment (TME) analysis following therapeutic interventions can identify response mechanisms, informing design of effective combinations. We provide a reference single-cell dataset from tumor-infiltrating leukocytes (TILs) from a human neoadjuvant clinical trial comparing the granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting allogeneic PDAC vaccine GVAX alone, in combination with anti-PD1 or with both anti-PD1 and CD137 agonist. Treatment with GVAX and anti-PD-1 led to increased CD8<sup>+</sup> T cell activation and expression of cytoskeletal and extracellular matrix (ECM)-interacting components. Addition of CD137 agonist increased abundance of clonally expanded CD8<sup>+</sup> T cells and increased immunosuppressive TREM2 signaling in tumor associated macrophages (TAMs), identified by comparison of ligand-receptor networks, corresponding to changes in metabolism and ECM interactions. These findings associate therapy with GVAX, anti-PD1, and CD137 agonist with enhanced CD8<sup>+</sup> T cell function while inducing alternative immunosuppressive pathways in patients with PDAC.
Authors
- Qingfeng Zhu (ORCID: https://orcid.org/0000-0001-7871-3359)
- Rulin Wang (ORCID: https://orcid.org/0009-0005-3509-4291)
- Su Jin Lim (ORCID: https://orcid.org/0000-0001-5532-9610)
- Jacquelyn W. Zimmerman (ORCID: https://orcid.org/0000-0002-7775-2943)
- Jennifer H. Elisseeff (ORCID: https://orcid.org/0000-0002-5066-1996)
- Logan L Engle
- Jacob T. Mitchell (ORCID: https://orcid.org/0000-0002-5370-9692)
- Guanglan Mo (ORCID: https://orcid.org/0009-0003-6519-3675)
- Robert A. Anders (ORCID: https://orcid.org/0000-0002-2363-9072)
- Elana J. Fertig (ORCID: https://orcid.org/0000-0003-3204-342X)
- Joseph A. Tandurella (ORCID: https://orcid.org/0000-0002-5806-6681)
- Ludmila Danilova (ORCID: https://orcid.org/0000-0003-2813-3094)
- Ajay Vaghasia (ORCID: https://orcid.org/0000-0002-4498-0966)
- Sarah Mitchell
- Emily F. Davis-Marcisak (ORCID: https://orcid.org/0000-0001-8624-1013)
- Li Pan (ORCID: https://orcid.org/0000-0003-3720-5504)
- Yao−Zhong Xu (ORCID: https://orcid.org/0000-0002-5713-8030)
- Janelle M. Montagne (ORCID: https://orcid.org/0000-0002-8113-1373)
- Won Jin Ho (ORCID: https://orcid.org/0000-0003-2644-5086)
- Eric S. Christenson (ORCID: https://orcid.org/0000-0001-5261-6083)
- Elizabeth M. Jaffee (ORCID: https://orcid.org/0000-0003-3841-6549)
- Dimitrios N. Sidiropoulos (ORCID: https://orcid.org/0000-0001-5716-3917)
- Jessica Gai
- Melanie Loth (ORCID: https://orcid.org/0000-0003-2717-8258)
- Wenpin Hou (ORCID: https://orcid.org/0000-0003-0972-2192)
- Alexander V. Favorov (ORCID: https://orcid.org/0000-0003-2595-1091)
- Atul Deshpande (ORCID: https://orcid.org/0000-0001-5144-6924)
- Luciane T. Kagohara (ORCID: https://orcid.org/0000-0003-1706-0950)
- Srinivasan Yegnasubramanian (ORCID: https://orcid.org/0000-0003-0744-6606)
- Daniel Bergman (ORCID: https://orcid.org/0000-0002-2166-6616)
- Lei Zheng (ORCID: https://orcid.org/0000-0003-4163-2541)
- Rui Zhang (ORCID: https://orcid.org/0000-0003-4690-3945)
- Hao Wang (ORCID: https://orcid.org/0000-0002-6214-606X)
- Benjamin Green (ORCID: https://orcid.org/0000-0002-2461-1274)
Institutions
- Bloomberg (United States) (US)
- Johns Hopkins University (US)
- Johns Hopkins Medicine (US)
- Convergence (US)
- Vavilov Institute of General Genetics (RU)
- Sidney Kimmel Comprehensive Cancer Center (US)
Publication Details
- Journal
- iScience
- Published
- 2024-12-10
- DOI
- https://doi.org/10.1016/j.isci.2024.111569
- Citations
- 10
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 2.83
Funders
- Amgen
- Bristol-Myers Squibb
- American Association of Immunologists
- Sanofi
- Lustgarten Foundation
- Exelixis
- National Institutes of Health
- Genentech
- Sidney Kimmel Comprehensive Cancer Center
- National Cancer Institute