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

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.