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. Macrophages in patients with early disease recurrence resided in a dysfunctional state bearing hallmarks of chronic interferon-signalling – frequently residing near CD8+ T-cell–DC dyads. Besides known immune-suppressive molecules such as IDO and PD-L1, paracortex macrophages and DCs in patients with recurrence expressed high levels of the secreted phospholipase PLA2G2D across different cancer types.

In addition, PLA2G2D was upregulated in non-small cell lung cancer patients upon acquired resistance to anti-PD-1 immunotherapy. Importantly, PLA2G2D loss-of-function or therapeutic inhibition markedly improved survival in tumor-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-tumor immunity and identifies PLA2G2D as a target for cancer immunotherapy.