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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE333464 | GEO | 2026/06/23

REPOSITORIES: GEO

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Project description:Current cancer immunotherapies can induce tumor regression, although responses are often not durable for reasons that are incompletely understood. Apart from activating pre-existing tumor-infiltrating T cells, recent studies have highlighted the importance of enforcing a systemic immune response from tumor-draining lymph nodes (TDLNs). However, mechanisms driving immune suppression in TDLNs remain poorly studied. We applied spatial proteogenomics on melanoma TDLNs and identified striking 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 a specific cellular interaction network in the lymph node paracortex, consisting 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. 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.

Project description:Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related mortality. CRC can be classified into DNA mismatch repair proficient (MMRp) and deficient (MMRd) subtypes, with only ~50% of MMRd tumours responding to immunotherapy. Tumour architecture is spatially heterogeneous, ranging from the necrotic core to the invasive front, accompanied by diverse stromal and immune responses that influence tumour progression and treatment outcomes. To explore the spatial organisation of the tumour-immune microenvironment, we profiled the expression of ~1,000 genes in 846,469 cells from 23 tumour and normal tissue samples using the CosMx Spatial Molecular Imager (SMI). Using a custom bioinformatic pipeline, we performed quality control, cell type annotation, identified 9 spatial niches and provide an interactive web application to explore this data. Spatial niches included normal colonic crypts, tumour masses, neutrophil-rich regions, and lymphoid aggregates. Differential gene expression analysis revealed niche-specific changes to chemokine signalling, T cell infiltration and myeloid cell polarisation could either support or inhibit tumours depending on the niche. To expand the analysis, we integrated public single-cell RNA-Seq datasets, identifying increased tumour stemness in samples with higher neutrophil content that appeared to be driven by inflammation-mediated stromal reprogramming. Additionally, samples enriched in lymphoid aggregates, as defined by a spatial lymphoid aggregate signature, displayed heightened interferon signalling and an increased abundance of proliferating B cells. Finally, we identify gene expression patterns that distinguish tumour cells from normal epithelial cells within tumours. Our analysis reveals that many of the most pronounced changes in tumour gene expression originate from alterations in the tumour microenvironment, while also revealing tumour-intrinsic gene expression. By studying the spatial niches of CRC, we reveal niche-specific dynamics that drive tumours through innate stromal signalling and suggest both tumour-specific and stromally-mediated potential therapeutic targets.

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

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