PLA2G2D identified as a new lymph-node immune checkpoint that hampers anti-cancer T-cell activity
Researchers discovered that the secreted enzyme PLA2G2D, produced by macrophages in tumour-draining lymph nodes, suppresses early CD8+ T-cell proliferation and promotes tumor growth; blocking it curtails tumors and works synergistically with anti-PD-1 therapy.
Using imaging mass cytometry and targeted spatial transcriptomics, the team mapped tumour-draining lymph nodes from melanoma patients and identified a paracortical neighbourhood enriched in activated CD8+ T cells adjacent to myeloid cells that secrete high levels of PLA2G2D, a secreted phospholipase linked to poor prognosis. In mouse models, loss-of-function or neutralising antibodies against PLA2G2D markedly slowed growth of colorectal and melanoma tumours by lifting a direct suppression of early T-cell proliferation.
Single-cell RNA-sequencing showed PLA2G2D expression is confined to a specific macrophage subset resembling tissue-zone macrophages. Anti-PLA2G2D treatment expanded tumour-specific CD8+ T cells in lymph nodes, blood and tumours, and its efficacy required CD8+ cells. Importantly, PLA2G2D and PD-1 act as non-redundant checkpoints; their combined inhibition enhanced tumour control in both murine and humanised models, highlighting a novel target for cancer immunotherapy.
Why it matters
Blocking PLA2G2D could boost the effectiveness of existing cancer immunotherapies by restoring T-cell activity.
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