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

Abstract

Systemic anti-tumour immunity results from T cell priming in tumour-draining lymph nodes (TDLNs)1, 2, 3–4. Although the suppression of T cells in tumours is well characterized5, 6, 7–8, 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. A specific population of macrophages that express high levels of the enzyme PLA2G2D in tumour-draining lymph nodes is associated with poor prognosis in patients, and inhibiting PLA2G2D improves anti-tumour immunity in mouse models.