PLA2G2D in tumour-draining lymph nodes regulates anti-tumour immunity.

Authors

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

Published in

Nature. Sep 09, 2026. Epub Sep 09, 2026.

Abstract

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.

PMID:
42717091
Bibliographic data and abstract were imported from PubMed on 10 Sep 2026.

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