Journal article
Prostaglandin D2 axis impairs immunity against melanoma via dendritic cells and γδ T cells in middle-aged mice
The Journal of immunology (1950), Vol.215(2), vkaf288
02/09/2026
DOI: 10.1093/jimmun/vkaf288
PMID: 41149947
Abstract
The risk of developing melanoma increases with age. Although immune checkpoint blockade (ICB) therapy has shown considerable success, a significant portion of melanoma patients either fail to respond to ICB or eventually develop resistance. This leads to the urgent need for exploring novel treatments. Phospholipase A2 group IID (PLA2G2D) is an inducible enzyme found in myeloid cells, especially in aging dendritic cells (DCs), that exert an immunosuppressive effect by producing anti- or proinflammatory small lipid molecules, including prostaglandin D2 (PGD2). An aging-related increase of PLA2G2D-PGD2 expression makes this signaling a promising target for treating aging-associated diseases. The overexpression of hematopoietic PGD2 synthase identified in both human and mouse melanoma tissue further highlights the potential of PLA2G2D-PGD2-targeting therapy. In this study, we show that the absence of PLA2G2D or the PGD2 receptor, PTGDR, restricts primary tumor growth and lung metastasis of subcutaneously implanted melanoma, as demonstrated using middle-aged Pla2g2d-/- and Ptgdr-/- mice. These therapeutic benefits are linked to increased tumor infiltration of activated γδ T cells, which can be amplified in B16F10-bearing wild-type mice through the adoptive transfer of Ptgdr-/- DCs. These tumor-restraining effects were also confirmed in DC-specific PTGDR-deficient (zDCcrePtgdrfloxp) mice. Mechanistically, the enhanced production of IL-1β by Ptgdr-/- DCs contributes to the activation and accumulation of γδ T cells in tumor tissue. In summary, our findings highlight the effectiveness of targeting the PLA2G2D-PGD2/PTGDR axis to reprogram aging dendritic cells, thereby inhibiting melanoma progression and presenting a promising therapeutic target, particularly for elderly patients.
Details
- Title: Subtitle
- Prostaglandin D2 axis impairs immunity against melanoma via dendritic cells and γδ T cells in middle-aged mice
- Creators
- Ming Liu - First Affiliated Hospital of Guangzhou Medical UniversityHima Dhakal - University of LouisvilleHong Li - University of LouisvilleMakoto Murakami - The University of TokyoShuh Narumiya - Kyoto UniversityJun Yan - University of LouisvilleKavitha Yaddanapudi - University of LouisvilleStanley Perlman - University of IowaJian Zheng - University of Louisville
- Resource Type
- Journal article
- Publication Details
- The Journal of immunology (1950), Vol.215(2), vkaf288
- DOI
- 10.1093/jimmun/vkaf288
- PMID
- 41149947
- NLM abbreviation
- J Immunol
- ISSN
- 0022-1767
- eISSN
- 1550-6606
- Publisher
- OXFORD UNIV PRESS
- Grant note
- Center for Predictive Medicine supplementary funding GZNL2024A02004 / Major Project of Guangzhou National Laboratory R01 AI129269 / NIAID NIH HHS F1256 / University of Louisville start funding 2022YFF1203300 / the National Key Research and Development Program of China P01 AI060699 / NIAID NIH HHS F1260 / University of Louisville start funding P20GM135004 / Center for Cancer Immunology and Immunotherapy-Center of Biomedical Research Excellence
- Language
- English
- Electronic publication date
- 10/28/2025
- Date published
- 02/09/2026
- Academic Unit
- Microbiology and Immunology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Infectious Disease (Pediatrics)
- Record Identifier
- 9985019036502771
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