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

Current cancer immunotherapies can induce tumour regression, although responses are often not durable. Recent studies have highlighted the importance of enforcing a systemic immune response from tumour-draining lymph nodes (TDLNs). However, mechanisms driving immune suppression in TDLNs remain poorly studied. We applied spatial proteogenomics on melanoma TDLNs and identified regional differences in immune cell composition in lymph nodes from patients with long-term (>5 years) disease control compared to those with early (<2 years) disease recurrence. TDLNs from patients with a poor prognosis were characterized by the expansion of regulatory T cells (Tregs), dendritic cells (DCs), and macrophages interacting with cytotoxic CD8+ T cells. Targeted transcriptomics of cell types within this spatial neighbourhood revealed immunoregulatory myeloid cell phenotypes engaging with CD8+ T cells poised for exhaustion. Besides known immune-suppressive molecules such as IDO and PD-L1, paracortex macrophages and DCs in patients with recurrent disease expressed high levels of the secreted phospholipase PLA2G2D across different cancer types. Additionally, PLA2G2D was upregulated in non-small cell lung cancer patients who developed acquired resistance to anti-PD-1 immunotherapy. Importantly, PLA2G2D loss-of-function or therapeutic inhibition markedly improved survival in tumour-bearing mice and increased the efficacy of anti-PD-1 immunotherapy. Collectively, we show that in-depth spatial profiling of cancer patient TDLNs offers novel insights into systemic anti-tumour immunity and identifies PLA2G2D as a target for cancer immunotherapy.