PLA2G2D in tumour-draining lymph nodes regulates anti-tumour immunity
- Anneloes van Krimpen
- Julie Huang
- Mike Eterman
- Vivian Gerretsen
- Michihisa Umetani
- Josephine C. Janssen
- Menno van Nimwegen
- Nina Rozendaal
- Thierry P. P. van den Bosch
- Xinguo Jiang
- Kathryn Logronio
- Angela Z. Liu
- Yun-Ru Liu
- Yuki Nagasaki
- Makoto Murakami
- Anne Onrust-van Schoonhoven
- Asabi Leliveld
- Disha Vadgama
- Hedwig Langeveld
- Rogier van Wijck
- Eric Bindels
- Jan von der Thüsen
- Antien Mooyaart
- Febe van Maldegem
- Claudia M. Brenis
- Stijn Verwaerde
- Rudi W. Hendriks
- Bart N. Lambrecht
- Dirk J. Grünhagen
- Cornelis Verhoef
- Joachim G. J. V. Aerts
- Li-Fen Lee
- Kan V. Lu
- Ralph Stadhouders
- Floris Dammeijer
2026-09-09
Systemic anti-tumour immunity results from T cell priming in tumour-draining lymph nodes (TDLNs) 1–4 . Although the suppression of T cells in tumours is well characterized 5–8 , whether this occurs in TDLNs—and if so, through which mechanisms—remains poorly understood. Here, using imaging mass cytometry of TDLNs from patients with melanoma, we identify a spatial neighbourhood in the TDLN paracortex that is linked to the development of distant metastases. Targeted spatial transcriptomics of cells inside this neighbourhood revealed activated CD8 + T cells engaging with myeloid cells that expressed high levels of the immunosuppressive secretory phospholipase PLA2G2D. PLA2G2D + myeloid cells were substantially more abundant in TDLNs than they were in primary tumours or metastases. Genetic loss-of-function or antibody-mediated inhibition of PLA2G2D reduced tumour growth markedly, and single-cell transcriptomics in melanoma-bearing mice revealed that expression of Pla2g2d is confined to lymph-node macrophages. Mechanistically, PLA2G2D directly suppressed the early proliferation of T cells in vitro, and inhibiting PLA2G2D resulted in an expansion of tumour-specific T cells in TDLNs, leading to an increase in these T cells in the circulation and subsequently in tumours. Notably, PLA2G2D and PD-1 act as non-redundant immune checkpoints, with combination treatment showing additive or synergistic efficacy in humanized mice treated with human-specific antibodies. Collectively, our in-depth spatial profiling identifies PLA2G2D as a TDLN-centred targetable immune checkpoint for cancer immunotherapy.