NATURE Paper - Published 9.9.26 - Apeximmune

Nature | www.nature.com | 1 Article PLA2G2D in tumour-draining lymph nodes regulates anti-tumour immunity Anneloes van Krimpen 1,2,13 , Julie Huang 3,13 , Mike Eterman 1,2 , Vivian Gerretsen 1,2,4 , Michihisa Umetani 3,5 , Josephine C. Janssen 2,6 , Menno van Nimwegen 1 , Nina Rozendaal 1 , Thierry P. P. van den Bosch 7 , Xinguo Jiang 3 , Kathryn Logronio 3 , Angela Z. Liu 3 , Yun-Ru Liu 8 , Yuki Nagasaki 9 , Makoto Murakami 9 , Anne Onrust-Van Schoonhoven 1 , Asabi Leliveld 1 , Disha Vadgama 1 , Hedwig Langeveld 1 , Rogier van Wijck 7 , Eric Bindels 10 , Jan von der Thüsen 7 , Antien Mooyaart 7 , Febe van Maldegem 11 , Claudia M. Brenis 4,12 , Stijn Verwaerde 4,12 , Rudi W. Hendriks 1 , Bart N. Lambrecht 1,4,12 , Dirk J. Grünhagen 2,6 , Cornelis Verhoef 2,6 , Joachim G. J. V. Aerts 1,2 , Li-Fen Lee 3,14 ✉ , Kan V. Lu 3,14 ✉ , Ralph Stadhouders 1,2,14 ✉ & Floris Dammeijer 1,2,14 ✉ 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. T-cell-driven adaptive immune responses against cancer antigens are a cornerstone of effective tumour control, although immune check- point activation limits T cell activity. Studies in preclinical models and early findings in patients indicate that TDLNs are a primary source of tumour-reactive T cells 1–4,9,10 . Immune checkpoint inhibitors (ICIs), such as anti-PD-1 or anti-PD-L1, act in part by enhancing T cell prim- ing and differentiation, thereby inducing a systemic anti-tumour immune response that is crucial for therapy efficacy in multiple tumour types 4,11–14 . Despite the clinical success of ICIs, many patients do not respond, or develop adaptive immune resistance 15,16 . Although the molecular underpinnings of ICI resistance and T cell dysfunction in the tumour microenvironment (TME) have been widely studied, the mechanisms that underlie immune suppression in TDLNs remain mostly unknown. TDLN characteristics are associated with distant disease relapse after melanoma resection, suggesting that TDLNs have a role in generating systemic anti-tumour immunity 11,17 . Although several immune-suppressive pathways known from studies in tumours have been implicated (for example, upregulation of PD-L1), an in-depth https://doi.org/10.1038/s41586-026-10954-1 Received: 16 October 2024 Accepted: 24 July 2026 Published online: xx xx xxxx Open access Check for updates 1 Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. 2 Erasmus MC Cancer Institute, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. 3 Apeximmune Therapeutics, Burlingame, CA, USA. 4 Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGent Centre for Inflammation Research, Ghent, Belgium. 5 Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, USA. 6 Department of Surgical Oncology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. 7 Department of Pathology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. 8 Taipei Medical University, Taipei City, Taiwan. 9 Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. 10 Department of Haematology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. 11 Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Amsterdam, The Netherlands. 12 Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium. 13 These authors contributed equally: Anneloes van Krimpen, Julie Huang. 14 These authors jointly supervised this work: Li-Fen Lee, Kan V. Lu, Ralph Stadhouders, Floris Dammeijer. ✉ e-mail: llee@apeximmune.com; klu@apeximmune.com; r.stadhouders@erasmusmc.nl; f.dammeijer@erasmusmc.nl