Biomedical subjects

Matthew D Park

Publications and source records attributed to Matthew D Park.

3 recordsLinked to original sources

PubMed2026

A serpin-myeloid axis in pancreatic cancer heterogeneity and immune evasion.

Pancreatic ductal carcinoma (PDAC) is characterized by a highly immunosuppressive, extracellular matrix-rich microenvironment, yet tumours display marked heterogeneity1-4. This raises the question of whether immune resistance is a global tumour property or is organized within spatially restricted niches. Here, using Perturb-map spatial functional genomics, we determine how different genes shape the growth and cellular environments of PDAC clones across space and time. This analysis revealed early gene-driven remodelling of local immune neighbourhoods preceding late-stage spatial clonal dominance. We identify SERPINE1 (encoding plasminogen activator inhibitor 1 (PAI1)) and SERPINB2 (encoding PAI2) as dominant regulators of tumour microenvironment control and immune evasion. These serpins promote stabilization of fibrin-rich extracellular matrix niches that spatially retain and programme macrophages towards immunosuppressive states while excluding cytotoxic T cells. Loss of Serpine1 or Serpinb2, or pharmacological inhibition of PAI1 or CD18, improves tumour control in mice and synergizes with anti-PD-1. Multimodal spatial analysis of patient tumours revealed that immunosuppressive niches form around rare SERPINB2- and SERPINE1-expressing PDAC subpopulations, dominated by SPP1+/MARCO+ macrophages. These findings identify cancer-derived SERPINE1 and SERPINB2 as local spatial organizers of immune suppression, linking tumour-intrinsic heterogeneity to local microenvironmental control and immunotherapy resistance in PDAC.

Journal Article↗

PubMed2026

Dendritic cells control tertiary lymphoid structure development and maintenance in cancer.

Tertiary lymphoid structures (TLSs) are associated with immunotherapy response, yet the mechanisms controlling their formation and maintenance remain unclear. Using spatial transcriptomics and multiplex imaging across human tumors, we found that CCR7+ mature dendritic cells (DCs) accumulate in TLSs. In a mouse non-small cell lung cancer model that forms mature TLSs, we show that early TLS development requires interferon-γ (IFN-γ)-driven type 1 conventional dendritic cell (cDC1) maturation, migration to tumor-draining lymph nodes (tdLNs), and T cell recruitment. As tumors progress, TLSs persist independently of tdLN T cell egress, coinciding with cDC1 accumulation within intratumoral CCL19 stromal hubs. There, cDC1-major histocompatibility complex class 1 (MHC-I) and -MHC-II concomitant antigen presentation, along with CD40 signaling, sustain TLS, T follicular helper (TFH) cell pool, germinal centers, and tumor-specific immunoglobulin G (IgG). These findings highlight local mature cDC1s as key TLS orchestrators and potential targets to enhance antitumor TLS function.

Animals↗

PubMed2026

Plasma signals of lung tumor promotion for molecular cancer prevention.

Predicting lung cancer risk would enhance prevention trials. Although the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial demonstrated reduced lung cancer incidence with interleukin (IL)-1β inhibition, the high number needed to treat (NNT) to prevent lung cancer limits its use in unselected populations. Using machine learning, we identified a 14-protein plasma signature predicting lung cancer more than 5 years before diagnosis. The signature, validated across eight cohorts, was elevated in current smokers and individuals exposed to particulate matter (PM) and linked to lung myeloid and alveolar cells. In epidermal growth factor receptor (EGFR)-driven lung adenocarcinoma, diverse epithelial lineages converged on a keratin8+/claudin4+ alveolar transitional state (KAC), whose transcriptional programs correlated with signature emergence. Components of the signature were induced by PM, oncogenic EGFR, or IL-1β, whereas IL-1β inhibition restrained PM-driven KAC expansion and early tumorigenesis. In CANTOS, the signature identified individuals who seemed to benefit more from anti-IL-1β therapy, lowering the NNT threshold and nominating circulating signals of tumor promotion for prevention.

Humans↗