Journal article
Reversing immunosuppression in the tumor microenvironment of fibrolamellar carcinoma via PD-1 and IL-10 blockade
Scientific reports, Vol.14(1), 5109
03/01/2024
DOI: 10.1038/s41598-024-55593-6
PMCID: PMC10907637
PMID: 38429349
Abstract
Fibrolamellar carcinoma (FLC) is a rare liver tumor driven by the DNAJ-PKAc fusion protein that affects healthy young patients. Little is known about the immune response to FLC, limiting rational design of immunotherapy. Multiplex immunohistochemistry and gene expression profiling were performed to characterize the FLC tumor immune microenvironment and adjacent non-tumor liver (NTL). Flow cytometry and T cell receptor (TCR) sequencing were performed to determine the phenotype of tumor-infiltrating immune cells and the extent of T cell clonal expansion. Fresh human FLC tumor slice cultures (TSCs) were treated with antibodies blocking programmed cell death protein-1 (PD-1) and interleukin-10 (IL-10), with results measured by cleaved caspase-3 immunohistochemistry. Immune cells were concentrated in fibrous stromal bands, rather than in the carcinoma cell compartment. In FLC, T cells demonstrated decreased activation and regulatory T cells in FLC had more frequent expression of PD-1 and CTLA-4 than in NTL. Furthermore, T cells had relatively low levels of clonal expansion despite high TCR conservation across individuals. Combination PD-1 and IL-10 blockade signficantly increased cell death in human FLC TSCs. Immunosuppresion in the FLC tumor microenvironment is characterized by T cell exclusion and exhaustion, which may be reversible with combination immunotherapy.
Details
- Title: Subtitle
- Reversing immunosuppression in the tumor microenvironment of fibrolamellar carcinoma via PD-1 and IL-10 blockade
- Creators
- S. K. Daniel - University of WashingtonK. M. Sullivan - University of WashingtonL. K. Dickerson - University of WashingtonR. J.E. van den Bijgaart - Fred Hutch Cancer CenterA. F. Utria - University of WashingtonK. P. Labadie - University of WashingtonH. L. Kenerson - University of WashingtonX. Jiang - University of WashingtonK. S. Smythe - Fred Hutch Cancer CenterJ. S. Campbell - Fred Hutch Cancer CenterR. H. Pierce - Fred Hutch Cancer CenterT. S. Kim - University of WashingtonK. J. Riehle - University of WashingtonR. S. Yeung - University of WashingtonJ. A. Carter - University of WashingtonK. C. Barry - Fred Hutch Cancer CenterV. G. Pillarisetty - University of Washington
- Resource Type
- Journal article
- Publication Details
- Scientific reports, Vol.14(1), 5109
- DOI
- 10.1038/s41598-024-55593-6
- PMID
- 38429349
- PMCID
- PMC10907637
- NLM abbreviation
- Sci Rep
- ISSN
- 2045-2322
- eISSN
- 2045-2322
- Grant note
- St. Baldrick's Foundation (100006058) Cancer Research Institute (http://data.elsevier.com/vocabulary/SciValFunders/100000884) St. Baldrick's Foundation (http://data.elsevier.com/vocabulary/SciValFunders/100006058) Fibrolamellar Cancer Foundation (100007909) 4093 / Fibrolamellar Cancer Foundation (http://data.elsevier.com/vocabulary/SciValFunders/100007909) S10 OD016240 / National Institutes of Health (http://data.elsevier.com/vocabulary/SciValFunders/100000002) Fibrolamellar Cancer Foundation (http://data.elsevier.com/vocabulary/SciValFunders/100007909) National Institutes of Health (http://data.elsevier.com/vocabulary/SciValFunders/100000002) U.S. Department of Defense (http://data.elsevier.com/vocabulary/SciValFunders/100000005) CA180067 / U.S. Department of Defense (100000005)
- Language
- English
- Date published
- 03/01/2024
- Academic Unit
- Surgery
- Record Identifier
- 9985015818502771
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